Publications by authors named "M Lotze"

729 Publications

Priming of Peritoneal Tumor-Reactive Lymphocytes With a Potent Oncolytic Virus for Adoptive Cell Therapy.

Front Immunol 2021 18;12:610042. Epub 2021 Feb 18.

Departments of Surgery, University of Pittsburgh School of Medicine, and UPMC Hillman Cancer Center, Pittsburgh, PA, United States.

Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) achieves durable clinical benefit for patients from whom these cells can be derived in advanced metastatic melanoma but is limited in most solid tumors as a result of immune escape and exclusion. A tumor microenvironment (TME) priming strategy to improve the quantity and quality of TIL represents an important tactic to explore. Oncolytic viruses expressing immune stimulatory cytokines induce a potent inflammatory response that may enhance infiltration and activation of T cells. In this study, we examined the ability of an attenuated oncolytic vaccinia virus expressing IL15/IL15Rα (vvDD-IL15/Rα) to enhance recovery of lavage T cells in peritoneal carcinomatosis (PC). We found that intraperitoneal (IP) vvDD-IL15/Rα treatment of animals bearing PC resulted in a significant increase in cytotoxic function and memory formation in CD8 T cells in peritoneal fluid. Using tetramers for vaccinia virus B8R antigen and tumor rejection antigen p15E, we found that the expanded population of peritoneal CD8 T cells are specific for vaccinia or tumor with increased tumor-specificity over time, reinforced with viral clearance. Application of these vvDD-IL15/Rα induced CD8 T cells in ACT of a lethal model of PC significantly increased survival. In addition, we found in patients with peritoneal metastases from various primary solid tumors that peritoneal T cells could be recovered but were exhausted with infrequent tumor-reactivity. If clinically translatable, vvDD-IL15/Rα priming would greatly expand the number of patients with advanced metastatic cancers responsive to T cell therapy.
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http://dx.doi.org/10.3389/fimmu.2021.610042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930493PMC
February 2021

ASO Author Reflection: Viruses, the Lung, and Thoracic Neoplasms: Breaking Bad.

Ann Surg Oncol 2021 May 4;28(5):2728-2729. Epub 2021 Mar 4.

University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

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http://dx.doi.org/10.1245/s10434-020-09484-5DOI Listing
May 2021

Using motor imagery practice for improving motor performance - A review.

Brain Cogn 2021 Feb 27;150:105705. Epub 2021 Feb 27.

Functional Imaging Unit, Center for Diagnostic Radiology, University Medicine of Greifswald, Germany. Electronic address:

Motor imagery practice is a current trend, but there is a need for a systematic integration of neuroscientific advances in the field. In this review, we describe the technique of motor imagery practice and its neural representation, considering different fields of application. The current practice of individualized motor imagery practice schemes often lacks systematization and is mostly based on experience. We review literature related to motor imagery practice in order to identify relevant modulators of practice effects like previous experience in motor training and motor imagery practice, the type of motor task to be trained, and strategies to increase sensory feedback during physical practice. Relevant discrepancies are identified between neuroscientific findings and practical consideration of these findings. To bridge these gaps, more effort should be directed at analyzing the brain network activities related to practically relevant motor imagery practice interventions.
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http://dx.doi.org/10.1016/j.bandc.2021.105705DOI Listing
February 2021

Tactile acuity of fingertips and hand representation size in human Area 3b and Area 1 of the primary somatosensory cortex.

Neuroimage 2021 May 27;232:117912. Epub 2021 Feb 27.

Functional Imaging Unit, Center for Diagnostic Radiology, University Medicine of Greifswald, Walther-Rathenau-Str.46, D-17475 Greifswald, Germany. Electronic address:

Intracortical mapping in monkeys revealed a full body map in all four cytoarchitectonic subdivisions of the contralateral primary somatosensory cortex (S1), as well as positive associations between spatio-tactile acuity performance of the fingers and their representation field size especially within cytoarchitectonic Area 3b and Area 1. Previous non-invasive investigations on these associations in humans assumed a monotonous decrease of representation field size from index finger to little finger although the field sizes are known to change in response to training or in disease. Recent developments improved noninvasive functional mapping of S1 by a) adding a cognitive task during repetitive stimulation to decrease habituation to the stimuli, b) smaller voxel size of fMRI-sequences, c) surface-based analysis accounting for cortical curvature, and d) increase of spatial specificity for fMRI data analysis by avoidance of smoothing, partial volume effects, and pial vein signals. We here applied repetitive pneumatic stimulation of digit 1 (D1; thumb) and digit 5 (D5; little finger) on both hands to investigate finger/hand representation maps in the complete S1, but also in cytoarchitectonic Areas 1, 2, 3a, and 3b separately, in 21 healthy volunteers using 3T fMRI. The distances between activation maxima of D1 and D5 were evaluated by two independent raters, blinded for performance parameters. The fingertip representations showed a somatotopy and were localized in the transition region between the crown and the anterior wall of the post central gyrus agreeing with Area 1 and 3b. Participants were comprehensively tested for tactile performance using von Freyhair filaments to determine cutaneous sensory thresholds (CST) as well as grating orientation thresholds (GOT) and two-point resolution (TPD) for spatio-tactile acuity testing. Motor performance was evaluated with pinch grip performance (Roeder test). We found bilateral associations of D1-D5 distance for GOT thresholds and partially also for TPD in Area 3b and in Area 1, but not if using the complete S1 mask. In conclusion, we here demonstrate that 3T fMRI is capable to map associations between spatio-tactile acuity and the fingertip representation in Area 3b and Area 1 in healthy participants.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117912DOI Listing
May 2021

Fighting Fire With Fire: Oncolytic Virotherapy for Thoracic Malignancies.

Ann Surg Oncol 2021 May 11;28(5):2715-2727. Epub 2021 Feb 11.

Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Thoracic malignancies are associated with high mortality rates. Conventional therapy for many of the patients with thoracic malignancies is obviated by a high incidence of locoregional recurrence and distant metastasis. Fortunately, developments in immunotherapy provide effective strategies for both local and systemic treatments that have rapidly advanced during the last decade. One promising approach to cancer immunotherapy is to use oncolytic viruses, which have the advantages of relatively high tumor specificity, selective replication-mediated oncolysis, enhanced antigen presentation, and potential for delivery of immunogenic payloads such as cytokines, with subsequent elicitation of effective antitumor immunity. Several oncolytic viruses including adenovirus, coxsackievirus B3, herpes virus, measles virus, reovirus, and vaccinia virus have been developed and applied to thoracic cancers in preclinical murine studies and clinical trials. This review discusses the current state of oncolytic virotherapy in lung cancer, esophageal cancer, and metastatic malignant pleural effusions and considers its potential as an emergent therapeutic for these patients.
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http://dx.doi.org/10.1245/s10434-020-09477-4DOI Listing
May 2021

Gray Matter Brain Alterations in Temporomandibular Disorder Tested in a Population Cohort and Three Clinical Samples.

J Pain 2021 Jan 30. Epub 2021 Jan 30.

Functional Imaging Unit, Department of Diagnostic Radiology and Neuroradiology, University Medicine, Greifswald, Germany. Electronic address:

Temporomandibular pain (TMD) is a frequent symptom comprising pain around the mandibular jaw with a high dependence on stressors. Chronic pain has been associated with changes of the brains gray matter volume (GMV), but previous studies on GMV alterations associated with TMD have yielded contradictory results. This might be caused by divergent samples and study methods. We here tested GMV alterations using voxel based morphometry in three clinical samples (summing up to 47 TMD patients) and a population sample with 57 participants who indicated facial pain for the last 6 months. The GMV of pain patients was compared against age-matched and gender-matched participants without chronic pain (60 for the clinical sample comparison and 381 for the cohort sample comparison) who underwent the same assessments as the patient group (MRI measurements and data evaluation using CAT12). In a region of interest analysis, only the clinical samples showed an effect of decreased GMV in the anterior medial cingulate cortex reaching into the medial prefrontal cortex, known to be especially vulnerable for chronic pain gray matter volume reduction. The analysis of the population-based sample did not reveal relevant GMV differences. Overall, an important question remains as to whether most inconsistent results from voxel based morphometry-studies in chronic pain are related to chance results facilitated by small sample size and selection of patient samples. PERSPECTIVE: Using voxel based morphometry 2 samples with chronic temperomandibular pain were compared to controls investigating the brains GMV. Only the clinical sample showed a decrease in anterior cingulate GMV. Contradicting results on GMV loss in temperomandibular pain might be based on small samples in prior studies.
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http://dx.doi.org/10.1016/j.jpain.2021.01.003DOI Listing
January 2021

Fronto-parietal involvement in chronic stroke motor performance when corticospinal tract integrity is compromised.

Neuroimage Clin 2021 18;29:102558. Epub 2021 Jan 18.

University of South Australia, IIMPACT in Health, Adelaide, Australia.

Background: Preserved integrity of the corticospinal tract (CST) is a marker of good upper-limb behavior and recovery following stroke. However, there is less understanding of neural mechanisms that might help facilitate upper-limb motor recovery in stroke survivors with extensive CST damage.

Objective: The purpose of this study was to investigate resting state functional connectivity in chronic stroke survivors with different levels of CST damage and to explore neural correlates of greater upper-limb motor performance in stroke survivors with compromised ipsilesional CST integrity.

Methods: Thirty chronic stroke survivors (24 males, aged 64.7 ± 10.8 years) participated in this study. Three experimental sessions were conducted to: 1) obtain anatomical (T1, T2) structural (diffusion) and functional (resting state) MRI sequences, 2) determine CST integrity with transcranial magnetic stimulation (TMS) and conduct assessments of upper-limb behavior, and 3) reconfirm CST integrity status. Participants were divided into groups according to the extent of CST damage. Those in the extensive CST damage group did not show TMS evoked responses and had significantly lower ipsilesional fractional anisotropy.

Results: Of the 30 chronic stroke survivors, 12 were categorized as having extensive CST damage. Stroke survivors with extensive CST damage had weaker functional connectivity in the ipsilesional sensorimotor network and greater functional connectivity in the ipsilesional fronto-parietal network compared to those with preserved CST integrity. For participants with extensive CST damage, improved motor performance was associated with greater functional connectivity of the ipsilesional fronto-parietal network and higher fractional anisotropy of the ipsilesional rostral superior longitudinal fasciculus.

Conclusions: Stroke survivors with extensive CST damage have greater resting state functional connectivity of an ipsilesional fronto-parietal network that appears to be a behaviorally relevant neural mechanism that improves upper-limb motor performance.
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http://dx.doi.org/10.1016/j.nicl.2021.102558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841401PMC
January 2021

Intrapleural interleukin-2-expressing oncolytic virotherapy enhances acute antitumor effects and T-cell receptor diversity in malignant pleural disease.

J Thorac Cardiovasc Surg 2020 Dec 13. Epub 2020 Dec 13.

Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pa; Surgical Services Division, VAPHS, Pittsburgh, Pa. Electronic address:

Objective: The mainstay of treatment for patients with malignant pleural disease is fluid drainage and systemic therapy. A tumor-specific oncolytic virus or T-cell-activating interleukin-2 immunotherapy may provide an opportunity for local control. We previously developed a vaccinia virus-expressing interleukin-2, an oncolytic virus that mediated tumor regression in preclinical peritoneal tumor models with expansion of tumor-infiltrating lymphocytes. We evaluated the antitumor efficacy and immune modulatory effects of vaccinia virus-expressing interleukin-2 in malignant pleural disease.

Methods: A murine model of malignant pleural disease was established with percutaneous intrapleural deposition of the Lewis lung carcinoma cell line and monitored with bioluminescent imaging. After intrapleural or systemic administration of vaccinia viruses (vaccinia virus yellow fluorescent protein control, vaccinia virus-expressing interleukin-2), systemic anti-programmed cell death-1 antibody, or combination therapy (vaccinia virus-expressing interleukin-2 and anti-programmed cell death-1), tumor mass, immune cell infiltration, T-cell receptor diversity, and survival were assessed.

Results: Intrapleural vaccinia virus resulted in significant tumor regression compared with phosphate-buffered saline control (P < .05). Inclusion of the interleukin-2 transgene further increased intratumoral CD8 T cells (P < .01) and programmed cell death-1 expression on CD8 tumor-infiltrating lymphocytes (P < .001). Intrapleural vaccinia virus-expressing interleukin-2 was superior to systemic vaccinia virus-expressing interleukin-2, with reduced tumor burden (P < .0001) and improved survival (P < .05). Intrapleural vaccinia virus-expressing interleukin-2 alone or combined treatment with systemic anti-programmed cell death-1 reduced tumor burden (P < .01), improved survival (P < .01), and increased intratumoral αβ T-cell receptor diversity (P < .05) compared with systemic anti-programmed cell death-1 monotherapy.

Conclusions: Intrapleural vaccinia virus-expressing interleukin-2 reduced tumor burden and enhanced survival in a murine malignant pleural disease model. Increased CD8 tumor-infiltrating lymphocytes and αβ T-cell receptor diversity are associated with enhanced response. Clinical trials will enable assessment of intrapleural vaccinia virus-expressing interleukin-2 therapy in patients with malignant pleural disease.
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http://dx.doi.org/10.1016/j.jtcvs.2020.11.160DOI Listing
December 2020

Modifications in fMRI Representation of Mental Rotation Following a 6 Week Graded Motor Imagery Training in Chronic CRPS Patients.

J Pain 2021 Jan 6. Epub 2021 Jan 6.

Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Germany. Electronic address:

Complex regional pain syndrome (CRPS) is a neuropathic pain condition that is difficult to treat. For behavioral interventions, graded motor imagery (GMI) showed relevant effects, but underlying neural substrates in patient groups have not been investigated yet. A previous study investigating differences in the representation of a left/right hand judgment task demonstrated less recruitment of subcortical structures, such as the putamen, in CRPS patients than in healthy controls. In healthy volunteers, the putamen activity increased after a hand judgment task training. In order to test for longitudinal effects of GMI training, we investigated 20 CRPS patients in a wait-list crossover design with 3 evaluation time points. Patients underwent a 6 week GMI treatment and a 6 week waiting period in a randomized group assignment and treatment groups were evaluated by a blinded rater. When compared to healthy matched controls at baseline, CRPS patients showed less functional activation in areas processing visual input, left sensorimotor cortex, and right putamen. Only GMI treatment, but not the waiting period showed an effect on movement pain and hand judgment task performance. Regression analyses revealed positive associations of movement pain with left anterior insula activation at baseline. Right intraparietal sulcus activation change during GMI was associated with a gain in performance of the hand judgment task. The design used here is reliable for investigating the functional representation of the hand judgment task in an intervention study. PERSPECTIVE: Twenty chronic CRPS patients underwent a 6 week GMI intervention in a randomized wait-list crossover design. functional MRI was tested pre and post for the hand lateralization task which improved over GMI but not over WAITING. Performance gain was positively related to right parietal functional MRI activation.
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http://dx.doi.org/10.1016/j.jpain.2020.12.003DOI Listing
January 2021

Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer.

J Immunother 2021 Feb-Mar 01;44(2):49-62

DAMP Laboratory, Department of Surgery.

Risk factors for colorectal cancer (CRC) include proinflammatory diets, sedentary habits, and obesity, in addition to genetic syndromes that predispose individuals to this disease. Current treatment relies on surgical excision and cytotoxic chemotherapies. There has been a renewed interest in immunotherapy as a treatment option for CRC given the success in melanoma and microsatellite instable (MSI) CRC. Immunotherapy with checkpoint inhibitors only plays a role in the 4%-6% of patients with MSIhigh tumors and even within this subpopulation, response rates can vary from 30% to 50%. Most patients with CRC do not respond to this modality of treatment, even though colorectal tumors are frequently infiltrated with T cells. Tumor cells limit apoptosis and survive following intensive chemotherapy leading to drug resistance and induction of autophagy. Pharmacological or molecular inhibition of autophagy improves the efficacy of cytotoxic chemotherapy in murine models. The microbiome clearly plays an etiologic role, in some or most colon tumors, realized by elegant findings in murine models and now investigated in human clinical trials. Recent results have suggested that cancer vaccines may be beneficial, perhaps best as preventive strategies. The search for therapies that can be combined with current approaches to increase their efficacy, and new knowledge of the biology of CRC are pivotal to improve the care of patients suffering from this disease. Here, we review the basic immunobiology of CRC, current "state-of-the-art" immunotherapies and define those areas with greatest therapeutic promise for the future.
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http://dx.doi.org/10.1097/CJI.0000000000000357DOI Listing
June 2020

Corrigendum: Longitudinal Analysis of T and B Cell Receptor Repertoire Transcripts Reveal Dynamic Immune Response in COVID-19 Patients.

Front Immunol 2020 21;11:633815. Epub 2020 Dec 21.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

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http://dx.doi.org/10.3389/fimmu.2020.633815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780884PMC
December 2020

The Unknown Unknowns: Recovering Gamma-Delta T Cells for Control of Human Immunodeficiency Virus (HIV).

Viruses 2020 12 17;12(12). Epub 2020 Dec 17.

Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Recent advances in γδ T cell biology have focused on the unique attributes of these cells and their role in regulating innate and adaptive immunity, promoting tissue homeostasis, and providing resistance to various disorders. Numerous bacterial and viral pathogens, including human immunodeficiency virus-1 (HIV), greatly alter the composition of γδ T cells in vivo. Despite the effectiveness of antiretroviral therapy (ART) in controlling HIV and restoring health in those affected, γδ T cells are dramatically impacted during HIV infection and fail to reconstitute to normal levels in HIV-infected individuals during ART for reasons that are not clearly understood. Importantly, their role in controlling HIV infection, and the implications of their failure to rebound during ART are also largely unknown and understudied. Here, we review important aspects of human γδ T cell biology, the effector and immunomodulatory properties of these cells, their prevalence and function in HIV, and their immunotherapeutic potential.
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http://dx.doi.org/10.3390/v12121455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766279PMC
December 2020

HMGB1 as a potential biomarker and therapeutic target for severe COVID-19.

Heliyon 2020 Dec 7;6(12):e05672. Epub 2020 Dec 7.

Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA.

COVID-19 has attracted global attention due to its rapid spread around the world with substantial morbidity and associated mortality. Severe COVID-19 can be complicated by the acute respiratory distress syndrome, sepsis and septic shock leading to death. These complications are thought to result from an overactivation of the immune system, leading to a cytokine storm syndrome associated with multiple organ failure. Here, we report that high mobility group box 1 (HMGB1), a prototypical damage-associated molecular pattern (DAMP) and a central mediator of lethal inflammation, could be a potential target for innovative therapeutic strategies for COVID-19. Serum HMGB1 in severe COVID-19 patients is elevated (189.40 ± 140.88 ng/ml). Exogenous HMGB1 induces the expression of SARS-CoV-2 entry receptor ACE2 in alveolar epithelial cells in an AGER-dependent manner. Importantly, genetic (using AGER siRNA) or pharmacological (using glycyrrhizin, chloroquine, hydroxychloroquine, and FPS-ZM1) inhibition of the HMGB1-AGER pathway blocks ACE2 expression. Thus, HMGB1 inhibitors are likewise promising drug candidates for the treatment of patients suffering from COVID-19.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720697PMC
December 2020

Multimodal Sensory-Spatial Integration and Retrieval of Trained Motor Patterns for Body Coordination in Musicians and Dancers.

Front Psychol 2020 17;11:576120. Epub 2020 Nov 17.

Functional Imaging Unit, Diagnostic Radiology and Neuroradiology, University of Greifswald, Greifswald, Germany.

Dancers and musicians are experts in spatial and temporal processing, which allows them to coordinate movement with music. This high-level processing has been associated with structural and functional adaptation of the brain for high performance sensorimotor integration. For these integration processes, adaptation does not only take place in primary and secondary sensory and motor areas but also in tertiary brain areas, such as the lateral prefrontal cortex (lPFC) and the intraparietal sulcus (IPS), providing vital resources for highly specialized performance. Here, we review evidence for the role of these brain areas in multimodal training protocols and integrate these findings into a new model of sensorimotor processing in complex motor learning.
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http://dx.doi.org/10.3389/fpsyg.2020.576120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704436PMC
November 2020

Outcomes of Neoadjuvant Chemotherapy Versus Chemoradiation in Localized Pancreatic Cancer: A Case-Control Matched Analysis.

Ann Surg Oncol 2020 Nov 24. Epub 2020 Nov 24.

Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.

Background: Neoadjuvant therapy is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC). It is unknown whether neoadjuvant chemoradiotherapy is more effective than chemotherapy (NCRT vs. NAC). We aim to compare pathological and survival outcomes of NCRT and NAC in patients with PDAC.

Patients And Methods: Single-center analysis of PDAC patients treated with NCRT or NAC followed by resection between December 2008 and December 2018 was performed. Average treatment effect (ATE) was estimated after case-control matching using Mahalanobis distance nearest-neighbor matching. Inverse probability weighted estimates (IPWE)-based ATE was estimated for disease-free survival (DFS) and overall survival (OS).

Results: Among the 418 patients (mean age 66.8 years, 51% female) included in the study, 327 received NAC and 91 received NCRT. NCRT patients had higher rates of locally advanced disease, number of neoadjuvant chemotherapy cycles, more chemotherapy regimen crossover (gemcitabine and 5-FU based), and were more likely to undergo open surgical procedures and/or vascular resection (all p < 0.05). After matched analysis, NCRT was associated with a significant reduction in lymph node positive disease [ATE = (-)0.24, p = 0.007] and lymphovascular invasion [ATE = (-)0.20, p = 0.02]. While NCRT was associated with significantly improved DFS by 9.5 months (p = 0.006), it did not affect OS by IPWE-based ATE after adjusting for adjuvant therapy (ATE = 5.5 months; p = 0.32).

Conclusion: Compared with NAC alone, NCRT is associated with improved pathologic surrogates and disease-free survival, but not overall survival in patients with PDAC.
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http://dx.doi.org/10.1245/s10434-020-09391-9DOI Listing
November 2020

Serum IL27 in Relation to Risk of Hepatocellular Carcinoma in Two Nested Case-Control Studies.

Cancer Epidemiol Biomarkers Prev 2021 Feb 17;30(2):388-395. Epub 2020 Nov 17.

UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.

Background: IL27 mRNA is highly enriched in the tissue of hepatocellular carcinoma. Overexpression of IL27 gene has been found to increase T-cell expression of inhibitory receptors, an immunosuppressive feature in tumor microenvironment, that promotes the development of hepatocellular carcinoma.

Methods: Two parallel case-control studies of hepatocellular carcinoma, each with 100 case-control pairs were conducted in the Singapore Chinese Health Study and the Shanghai Cohort Study to examine the association between serum IL27 levels and risk of developing hepatocellular carcinoma.

Results: The IL27 concentrations were significantly elevated in sera collected from study participants 4 to 5 years prior to the diagnosis of hepatocellular carcinoma in both cohort studies. Compared with the lowest tertile of IL27, odds ratios (OR) of hepatocellular carcinoma for the highest tertile of IL27 was 46.08 [95% confidence interval (CI), 4.68-453.86] in the Singapore Chinese Health Study and 19.09 (95% CI, 3.81-95.57) in the Shanghai Cohort Study (both <0.001). The corresponding ORs in both cohort studies were 42.47 (95% CI, 8.30-217.40) among individuals negative for hepatitis B surface antigen (HBsAg) and 242.46 (95% CI, 38.42-1,529.01) among those positive for HBsAg compared with the lowest tertile of interleukin-27 and negative HBsAg.

Conclusions: Levels of IL27 in prediagnostic sera were significantly associated with increased risk of hepatocellular carcinoma development.

Impact: IL27, through its immunosuppressive property, may play a significant role in the development of hepatocellular carcinoma. Serum levels of IL27 may be used as a biomarker for prediction of hepatocellular carcinoma development.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867592PMC
February 2021

Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.

J Immunother Cancer 2020 11;8(2)

Department of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-001583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670953PMC
November 2020

Income is associated with hippocampal/amygdala and education with cingulate cortex grey matter volume.

Sci Rep 2020 11 2;10(1):18786. Epub 2020 Nov 2.

Functional Imaging Unit, Center for Diagnostic Radiology and Neuroradiology, Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Walther-Rathenau-Str.46, 17475, Greifswald, Germany.

Income and education are both elements of a person's socioeconomic status, which is predictive of a broad range of life outcomes. The brain's gray matter volume (GMV) is influenced by socioeconomic status and mediators related to an unhealthy life style. We here investigated two independent general population samples comprising 2838 participants (all investigated with the same MRI-scanner) with regard to the association of indicators of the socioeconomic status and gray matter volume. Voxel-based morphometry without prior hypotheses revealed that years of education were positively associated with GMV in the anterior cingulate cortex and net-equivalent income with gray matter volume in the hippocampus/amygdala region. Analyses of possible mediators (alcohol, cigarettes, body mass index (BMI), stress) revealed that the relationship between income and GMV in the hippocampus/amygdala region was partly mediated by self-reported stressors, and the association of years of education with GMV in the anterior cingulate cortex by BMI. These results corrected for whole brain effects (and therefore not restricted to certain brain areas) do now offer possibilities for more detailed hypotheses-driven approaches.
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http://dx.doi.org/10.1038/s41598-020-75809-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608615PMC
November 2020

Longitudinal Analysis of T and B Cell Receptor Repertoire Transcripts Reveal Dynamic Immune Response in COVID-19 Patients.

Front Immunol 2020 30;11:582010. Epub 2020 Sep 30.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Severe COVID-19 is associated with profound lymphopenia and an elevated neutrophil to lymphocyte ratio. We applied a novel dimer avoidance multiplexed polymerase chain reaction next-generation sequencing assay to analyze T (TCR) and B cell receptor (BCR) repertoires. Surprisingly, TCR repertoires were markedly diminished during the early onset of severe disease but recovered during the convalescent stage. Monitoring TCR repertoires could serve as an indicative biomarker to predict disease progression and recovery. Panoramic concurrent assessment of BCR repertoires demonstrated isotype switching and a transient but dramatic early IgA expansion. Dominant B cell clonal expansion with decreased diversity occurred following recovery from infection. Profound changes in T cell homeostasis raise critical questions about the early events in COVID-19 infection and demonstrate that immune repertoire analysis is a promising method for evaluating emergent host immunity to SARS-CoV-2 viral infection, with great implications for assessing vaccination and other immunological therapies.
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http://dx.doi.org/10.3389/fimmu.2020.582010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561365PMC
November 2020

Cortical thickness and resting-state cardiac function across the lifespan: A cross-sectional pooled mega-analysis.

Psychophysiology 2020 Oct 10. Epub 2020 Oct 10.

Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.
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http://dx.doi.org/10.1111/psyp.13688DOI Listing
October 2020

HMGB1 Promotes Myeloid Egress and Limits Lymphatic Clearance of Malignant Pleural Effusions.

Front Immunol 2020 4;11:2027. Epub 2020 Sep 4.

Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, United States.

Pleural effusions, when benign, are attributed to cardiac events and suffusion of fluid within the pleural space. When malignant, lymphatic obstruction by tumor and failure to absorb constitutively produced fluid is the predominant formulation. The prevailing view has been challenged recently, namely that the lymphatics are only passive vessels, carrying antigenic fluid to secondary lymphoid sites. Rather, lymphatic vessels can be a selective barrier, efficiently coordinating egress of immune cells and factors within tissues, limiting tumor spread and immune pathology. An alternative explanation, offered here, is that damage associated molecular pattern molecules, released in excess, maintain a local milieu associated with recruitment and retention of immune cells associated with failed lymphatic clearance and functional lymphatic obstruction. We found that levels of high mobility group box 1 (HMGB1) were equally elevated in both benign and malignant pleural effusions (MPEs) and that limited diversity of T cell receptor expressing gamma and delta chain were inversely associated with these levels in MPEs. Acellular fluid from MPEs enhanced γδ T cell proliferation , while inhibiting cytokine production from γδ T cells and monocytes as well as restricting monocyte chemotaxis. Novel therapeutic strategies, targeting HMGB1 and its neutralization in such effusions as well as direct delivery of immune cells into the pleural space to reconstitute normal physiology should be considered.
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http://dx.doi.org/10.3389/fimmu.2020.02027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498625PMC
September 2020

Actin-binding protein profilin1 promotes aggressiveness of clear-cell renal cell carcinoma cells.

J Biol Chem 2020 11 3;295(46):15636-15649. Epub 2020 Sep 3.

Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. Electronic address:

Clear-cell renal cell carcinoma (ccRCC), the most common subtype of renal cancer, has a poor clinical outcome. A hallmark of ccRCC is genetic loss-of-function of (von Hippel-Lindau) that leads to a highly vascularized tumor microenvironment. Although many ccRCC patients initially respond to antiangiogenic therapies, virtually all develop progressive, drug-refractory disease. Given the role of dysregulated expressions of cytoskeletal and cytoskeleton-regulatory proteins in tumor progression, we performed analyses of The Cancer Genome Atlas (TCGA) transcriptome data for different classes of actin-binding proteins to demonstrate that increased mRNA expression of profilin1 (Pfn1), Arp3, cofilin1, Ena/VASP, and CapZ, is an indicator of poor prognosis in ccRCC. Focusing further on Pfn1, we performed immunohistochemistry-based classification of Pfn1 staining in tissue microarrays, which indicated Pfn1 positivity in both tumor and stromal cells; however, the vast majority of ccRCC tumors tend to be Pfn1-positive selectively in stromal cells only. This finding is further supported by evidence for dramatic transcriptional up-regulation of Pfn1 in tumor-associated vascular endothelial cells in the clinical specimens of ccRCC. studies support the importance of Pfn1 in proliferation and migration of RCC cells and in soluble Pfn1's involvement in vascular endothelial cell tumor cell cross-talk. Furthermore, proof-of-concept studies demonstrate that treatment with a novel computationally designed Pfn1-actin interaction inhibitor identified herein reduces proliferation and migration of RCC cells and RCC tumor growth Based on these findings, we propose a potentiating role for Pfn1 in promoting tumor cell aggressiveness in the setting of ccRCC.
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http://dx.doi.org/10.1074/jbc.RA120.013963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667959PMC
November 2020

Characteristics of Malignant Pleural Effusion Resident CD8 T Cells from a Heterogeneous Collection of Tumors.

Int J Mol Sci 2020 Aug 27;21(17). Epub 2020 Aug 27.

Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.

While T cell-based cancer immunotherapies have shown great promise, there remains a need to understand how individual metastatic tumor environments impart local T cell dysfunction. At advanced stages, cancers that metastasize to the pleural space can result in a malignant pleural effusion (MPE) that harbors abundant tumor and immune cells, often exceeding 10 leukocytes per liter. Unlike other metastatic sites, MPEs are readily and repeatedly accessible via indwelling catheters, providing an opportunity to study the interface between tumor dynamics and immunity. In the current study, we examined CD8 T cells within MPEs collected from patients with heterogeneous primary tumors and at various stages in treatment to determine (1) if these cells possess anti-tumor activity following removal from the MPE, (2) factors in the MPE that may contribute to their dysfunction, and (3) the phenotypic changes in T cell populations that occur following ex vivo expansion. Co-cultures of CD8 T cells with autologous CD45 tumor containing cells demonstrated cytotoxicity ( = 0.030) and IFNγ production ( = 0.003) that inversely correlated with percent of myeloid derived suppressor cells, lactate, and lactate dehydrogenase (LDH) within the MPE. Ex vivo expansion of CD8 T cells resulted in progressive differentiation marked by distinct populations expressing decreased CD45RA, CCR7, CD127, and increased inhibitory receptors. These findings suggest that MPEs may be a source of tumor-reactive T cells and that the cellular and acellular components suppress optimal function.
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http://dx.doi.org/10.3390/ijms21176178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503595PMC
August 2020

CDK1/2/5 inhibition overcomes IFNG-mediated adaptive immune resistance in pancreatic cancer.

Gut 2021 May 14;70(5):890-899. Epub 2020 Aug 14.

The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China

Objective: Adaptive immune resistance mediated by the cytokine interferon gamma (IFNG) still constitutes a major problem in cancer immunotherapy. We develop strategies for overcoming IFNG-mediated adaptive immune resistance in pancreatic ductal adenocarcinoma cancer (PDAC).

Design: We screened 429 kinase inhibitors for blocking IFNG-induced immune checkpoint (indoleamine 2,3-dioxygenase 1 (IDO1) and CD274) expression in a human PDAC cell line. We evaluated the ability of the cyclin-dependent kinase (CDK) inhibitor dinaciclib to block IFNG-induced and expression in 24 human and mouse cancer cell lines as well as in primary cancer cells from patients with PDAC or ovarian carcinoma. We tested the effects of dinaciclib on IFNG-induced signal transducer and activator of transcription 1 activation and immunological cell death, and investigated the potential utility of dinaciclib in combination with IFNG for pancreatic cancer therapy in vivo, and compared gene expression levels between human cancer tissues with patient survival times using the Cancer Genome Atlas datasets.

Results: Pharmacological (using dinaciclib) or genetic (using shRNA or siRNA) inactivation of CDK1/2/5 not only blocks JUN-dependent immune checkpoint expression, but also triggers histone-dependent immunogenic cell death in immortalised or primary cancer cells in response to IFNG. This dual mechanism turns an immunologically 'cold' tumour microenvironment into a 'hot' one, dramatically improving overall survival rates in mouse pancreatic tumour models (subcutaneous, orthotopic and transgenic models). The abnormal expression of CDK1/2/5 and IDO1 was associated with poor patient survival in several cancer types, including PDAC.

Conclusion: CDK1/2/5 kinase activity is essential for IFNG-mediated cancer immunoevasion. CDK1/2/5 inhibition by dinaciclib provides a novel strategy to overcome IFNG-triggered acquired resistance in pancreatic tumour immunity.
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http://dx.doi.org/10.1136/gutjnl-2019-320441DOI Listing
May 2021

The Neural Correlates of Face-Voice-Integration in Social Anxiety Disorder.

Front Psychiatry 2020 15;11:657. Epub 2020 Jul 15.

Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.

Faces and voices are very important sources of threat in social anxiety disorder (SAD), a common psychiatric disorder where core elements are fears of social exclusion and negative evaluation. Previous research in social anxiety evidenced increased cerebral responses to negative facial or vocal expressions and also generally increased hemodynamic responses to voices and faces. But it is unclear if also the cerebral process of face-voice-integration is altered in SAD. Applying functional magnetic resonance imaging, we investigated the correlates of the audiovisual integration of dynamic faces and voices in SAD as compared to healthy individuals. In the bilateral midsections of the superior temporal sulcus (STS) increased integration effects in SAD were observed driven by greater activation increases during audiovisual stimulation as compared to auditory stimulation. This effect was accompanied by increased functional connectivity with the visual association cortex and a more anterior position of the individual integration maxima along the STS in SAD. These findings demonstrate that the audiovisual integration of facial and vocal cues in SAD is not only systematically altered with regard to intensity and connectivity but also the individual location of the integration areas within the STS. These combined findings offer a novel perspective on the neuronal representation of social signal processing in individuals suffering from SAD.
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http://dx.doi.org/10.3389/fpsyt.2020.00657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381153PMC
July 2020

Autophagy inhibition is the next step in the treatment of glioblastoma patients following the Stupp era.

Cancer Gene Ther 2020 Aug 5. Epub 2020 Aug 5.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

It has now been nearly 15 years since the last major advance in the treatment of patients with glioma. "The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity". Autophagy is primarily a survival pathway, literally self-eating, that is utilized in response to stress (such as radiation and chemotherapy), enabling clearance of effete protein aggregates and multimolecular assemblies. Promising results have been observed in patients with glioma for over a decade now when autophagy inhibition with chloroquine derivatives coupled with conventional therapy. The application of autophagy inhibitors, the role of immune cell-induced autophagy, and the potential role of novel cellular and gene therapies, should now be considered for development as part of this well-established regimen.
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http://dx.doi.org/10.1038/s41417-020-0205-8DOI Listing
August 2020

The modulating impact of cigarette smoking on brain structure in panic disorder: a voxel-based morphometry study.

Soc Cogn Affect Neurosci 2020 10;15(8):849-859

Department of Psychology, Humboldt-Universität zu Berlin, Berlin 10117, Germany.

Cigarette smoking increases the likelihood of developing anxiety disorders, among them panic disorder (PD). While brain structures altered by smoking partly overlap with morphological changes identified in PD, the modulating impact of smoking as a potential confounder on structural alterations in PD has not yet been addressed. In total, 143 PD patients (71 smokers) and 178 healthy controls (62 smokers) participated in a multicenter magnetic resonance imaging (MRI) study. T1-weighted images were used to examine brain structural alterations using voxel-based morphometry in a priori defined regions of the defensive system network. PD was associated with gray matter volume reductions in the amygdala and hippocampus. This difference was driven by non-smokers and absent in smoking subjects. Bilateral amygdala volumes were reduced with increasing health burden (neither PD nor smoking > either PD or smoking > both PD and smoking). As smoking can narrow or diminish commonly observed structural abnormalities in PD, the effect of smoking should be considered in MRI studies focusing on patients with pathological forms of fear and anxiety. Future studies are needed to determine if smoking may increase the risk for subsequent psychopathology via brain functional or structural alterations.
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http://dx.doi.org/10.1093/scan/nsaa103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543937PMC
October 2020

Neural substrates of long-term item and source memory for emotional associates: An fMRI study.

Neuropsychologia 2020 10 23;147:107561. Epub 2020 Jul 23.

Department of Biological Psychology and Affective Science, Faculty of Human Sciences, University of Potsdam, 14476, Potsdam, Germany; Faculty of Health Sciences Brandenburg, University of Potsdam, 14476, Potsdam, Germany. Electronic address:

Since Tulving's influential work on the distinction between familiarity and recollection-based retrieval, numerous studies have found evidence for differential contribution of these retrieval mechanisms on emotional episodic memory. Particularly, retrieval advantage for emotional, compared to neutral, information has been related to recollection-, but not familiarity-mediated processes. Neuroimaging studies suggest that this recollection-based retrieval for emotional information is related to stronger engagement of regions in the medial temporal lobe (MTL), posterior parietal cortex (PPC), and prefrontal cortex (PFC). In the present study, we investigated neural correlates related to long-term memory of neutral information that has been associated with emotional and neutral contexts, using functional magnetic resonance imaging (fMRI). During encoding, different neutral objects integrated with emotional or neutral scenes were presented. One week later, the encoded objects were intermixed with new ones and participants had to indicate whether the objects were previously seen or not, using the Remember/Know procedure (item memory). Furthermore, memory for the correct scene background category was also tested (contextual source memory). First, replicating previous findings, we observed a preference for recollection-dependent memory retrieval versus familiarity-dependent memory retrieval for those neutral objects encoded in emotional compared to neutral contexts. Second, consistent with these behavioral effects, objects encoded with emotional, compared to neutral, scenes produced larger memory-related activity in recollection-sensitive brain regions, including PPC and PFC regions. Third, correctly retrieved emotional compared to neutral contextual information was associated with increased activity in these brain areas. Together, these results suggest that memory for information encoded in emotional contexts is remarkably robust over time and mediated by recollection-based processes.
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http://dx.doi.org/10.1016/j.neuropsychologia.2020.107561DOI Listing
October 2020

Bi- and Tri-Specific T Cell Engager-Armed Oncolytic Viruses: Next-Generation Cancer Immunotherapy.

Biomedicines 2020 Jul 10;8(7). Epub 2020 Jul 10.

Icell Kealex Therapeutics, Houston, TX 77021, USA.

Oncolytic viruses (OVs) are potent anti-cancer biologics with a bright future, having substantial evidence of efficacy in patients with cancer. Bi- and tri-specific antibodies targeting tumor antigens and capable of activating T cell receptor signaling have also shown great promise in cancer immunotherapy. In a cutting-edge strategy, investigators have incorporated the two independent anti-cancer modalities, transforming them into bi- or tri-specific T cell engager (BiTE or TriTE)-armed OVs for targeted immunotherapy. Since 2014, multiple research teams have studied this combinatorial strategy, and it showed substantial efficacy in various tumor models. Here, we first provide a brief overview of the current status of oncolytic virotherapy and the use of multi-specific antibodies for cancer immunotherapy. We then summarize progress on BiTE and TriTE antibodies as a novel class of cancer therapeutics in preclinical and clinical studies, followed by a discussion of BiTE- or TriTE-armed OVs for cancer therapy in translational models. In addition, T cell receptor mimics (TCRm) have been developed into BiTEs and are expected to greatly expand the application of BiTEs and BiTE-armed OVs for the effective targeting of intracellular tumor antigens. Future applications of such innovative combination strategies are emerging as precision cancer immunotherapies.
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http://dx.doi.org/10.3390/biomedicines8070204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400484PMC
July 2020

Oncolytic virus promotes tumor-reactive infiltrating lymphocytes for adoptive cell therapy.

Cancer Gene Ther 2021 Feb 7;28(1-2):98-111. Epub 2020 Jul 7.

Department of Surgery, University of Pittsburgh School of Medicine, and UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Adoptive cell therapy (ACT) using tumor-specific tumor-infiltrating lymphocytes (TILs) has demonstrated success in patients where tumor-antigen specific TILs can be harvested from the tumor, expanded, and re-infused in combination with a preparatory regimen and IL2. One major issue for non-immunogenic tumors has been that the isolated TILs lack tumor specificity and thus possess limited in vivo therapeutic function. An oncolytic virus (OV) mediates an immunogenic cell death for cancer cells, leading to elicitation and dramatic enhancement of tumor-specific TILs. We hypothesized that the tumor-specific TILs elicited and promoted by an OV would be a great source for ACT for solid cancer. In this study, we show that a local injection of oncolytic poxvirus in MC38 tumor with low immunogenicity in C57BL/6 mice, led to elicitation and accumulation of tumor-specific TILs in the tumor tissue. Our analyses indicated that IL2-armed OV-elicited TILs contain lower quantities of exhausted PD-1Tim-3 CD8 T cells and regulatory T cells. The isolated TILs from IL2-expressing OV-treated tumor tissue retained high tumor specificity after expansion ex vivo. These TILs resulted in significant tumor regression and improved survival after adoptive transfer in mice with established MC38 tumor. Our study showcases the feasibility of using an OV to induce tumor-reactive TILs that can be expanded for ACT.
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http://dx.doi.org/10.1038/s41417-020-0189-4DOI Listing
February 2021