1,029 results match your criteria Cancer Immunol Res[Journal]


A genetic screen to identify gain- and loss-of-function modifications that enhance T-cell infiltration into tumors.

Cancer Immunol Res 2020 Jul 1. Epub 2020 Jul 1.

Holden Comprehensive Cancer Ctr., University of Iowa.

T cell-mediated cancer immunotherapies, including anti-PD-1 and CAR-T cells, are becoming standard treatments for many cancer types. CAR-T therapy, in particular, has been successful in treating circulating, but not solid, tumors. One challenge limiting immunotherapy success is that tumors lacking T-cell infiltration do not respond to treatment. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-20-0056DOI Listing

In human visualization of ibrutinib-induced CLL compartment shift.

Cancer Immunol Res 2020 Jun 24. Epub 2020 Jun 24.

Department of Medicine I, Medical University of Vienna

Bruton's tyrosine kinase inhibitor ibrutinib is effective in treating chronic lymphocytic leukemia (CLL). However, after ibrutinib treatment initiation, patients frequently experience an increase of CLL blood cell count. This phenomenon in clinical practice is thought to reflect a "compartment shift" of CLL cells from lymph nodes to the peripheral blood, but the actual shifting has not yet been demonstrated. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0880DOI Listing

Distinctive subpopulations of stromal cells are present in human lymph nodes infiltrated with melanoma.

Cancer Immunol Res 2020 Jun 24. Epub 2020 Jun 24.

Maurice Wilkins Centre & School of Biological Sciences, University of Auckland

Metastasis of human tumors to lymph nodes (LNs) is a universally negative prognostic factor. LN stromal cells (SCs) play a crucial role in enabling T cell responses, and since tumor metastases modulate their structure and function, this interaction may suppress immune responses to tumor antigens. The SC subpopulations that respond to infiltration of malignant cells into human LNs have not been defined. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0796DOI Listing

SRC-3 Functions as a Coactivator of T-bet by Regulating the Maturation and Antitumor Activity of Natural Killer Cells.

Cancer Immunol Res 2020 Jun 19. Epub 2020 Jun 19.

State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China.

Natural killer (NK)-cell development and maturation is a well-organized process. The steroid receptor coactivator 3 (SRC-3) is a regulator of the hematopoietic and immune systems; however, its role in NK cells is poorly understood. Here, SRC-3 displayed increased nuclear translocation in NK cells during terminal differentiation and upon inflammatory cytokine stimulation. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-20-0181DOI Listing

Identification of the cryptic HLA-I immunopeptidome.

Cancer Immunol Res 2020 Jun 19. Epub 2020 Jun 19.

Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg.

The success of cancer immunotherapy relies on the ability of cytotoxic T cells to specifically recognize and eliminate tumor cells based on peptides presented by HLA-I. Although the peptide epitopes that elicit the corresponding immune response often remain unidentified, it is generally assumed that neoantigens, due to tumor-specific mutations, are the most common targets. Here, we used a mass spectrometric approach to show an underappreciated class of epitopes that accounts for up to 15% of HLA-I peptides for certain HLA alleles in various tumors and patients. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0886DOI Listing

Radiotherapy Cooperates with IL15 to Induce Antitumor Immune Responses.

Cancer Immunol Res 2020 Jun 12. Epub 2020 Jun 12.

Department of Radiation Oncology, Weill Cornell Medicine, New York, New York.

Focal radiotherapy can promote cross-presentation of tumor antigens to T cells, but by itself, it is insufficient to induce therapeutically effective T-cell responses. The common gamma-chain cytokine IL15 promotes and sustains the proliferation and effector function of CD8 T cells but has limited activity against poorly immunogenic tumors that do not elicit significant spontaneous T-cell responses. Here, we show that radiotherapy and subcutaneous IL15 had complementary effects and induced CD8 T-cell-mediated tumor regression and long-term protective memory responses in two mouse carcinoma models unresponsive to IL15 alone. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0338DOI Listing

Immunotargeting of the xCT cystine/glutamate antiporter potentiates the efficacy of Her2-targeted immunotherapies in breast cancer.

Cancer Immunol Res 2020 Jun 12. Epub 2020 Jun 12.

Department of Molecular Biotechnology and Health Sciences, University of Turin.

Despite Her2-targeted therapies improving the outcome of Her2+ breast cancer, many patients experience resistance and metastatic progression. Cancer stem cells (CSCs) play a role in this resistance and progression, thus combining Her2-targeting with CSC inhibition could improve the management of Her2+ breast cancer. The cystine-glutamate antiporter xCT is overexpressed in mammary CSCs and is crucial for their redox balance, self-renewal and resistance to therapies, representing a potential target for breast cancer immunotherapy. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-20-0082DOI Listing

The Mincle/Syk/NF-κB Signaling Circuit Is Essential for Maintaining the Protumoral Activities of Tumor-Associated Macrophages.

Cancer Immunol Res 2020 Jun 12. Epub 2020 Jun 12.

Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.

Tumor-associated macrophages (TAM) have important roles in cancer progression, but the signaling behind the formation of protumoral TAM remains understudied. Here, by single-cell RNA sequencing, we revealed that the pattern recognition receptor Mincle was highly expressed in TAM and significantly associated with mortality in patients with non-small cell lung cancer. Cancer cells markedly induced Mincle expression in bone marrow-derived macrophages (BMDM), thus promoting cancer progression in invasive lung carcinoma LLC and melanoma B16F10 and Mincle was predominately expressed in the M2-like TAM in non-small cell lung carcinoma and LLC tumors, and silencing of Mincle unexpectedly promoted M1-like phenotypes Mechanistically, we discovered a novel Mincle/Syk/NF-κB signaling pathway in TAM needed for executing their TLR4-independent protumoral activities. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0782DOI Listing

Inflammation-Induced Abnormal Expression of Self-molecules on Epithelial Cells: Targets for Tumor Immunoprevention.

Cancer Immunol Res 2020 May 28. Epub 2020 May 28.

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Tumor-associated antigens (TAA) are self-molecules abnormally expressed on tumor cells, which elicit humoral and cellular immunity and are targets of immunosurveillance. Immunity to TAAs is found in some healthy individuals with no history of cancer and correlates positively with a history of acute inflammatory and infectious events and cancer risk reduction. This suggests a potential role in cancer immunosurveillance for the immune memory elicited against disease-associated antigens (DAA) expressed on infected and inflamed tissues that are later recognized on tumors as TAAs. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0870DOI Listing

ASC Modulates CTL Cytotoxicity and Transplant Outcome Independent of the Inflammasome.

Cancer Immunol Res 2020 May 22. Epub 2020 May 22.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8 T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11-deficient T cells. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0653DOI Listing

The Expression of Adenosine A2B Receptor on Antigen-Presenting Cells Suppresses CD8 T-cell Responses and Promotes Tumor Growth.

Cancer Immunol Res 2020 May 7. Epub 2020 May 7.

Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.

Accumulating evidence suggests that inhibiting adenosine-generating ecto-enzymes (CD39 and CD73) and/or adenosine A2A or A2B receptors (R) stimulates antitumor immunity and limits tumor progression. Although activating A2ARs or A2BRs causes similar immunosuppressive and protumoral functions, few studies have investigated the distinct role of A2BR in cancer. Here, we showed that A2BR expression by hematopoietic cells was primarily responsible for promoting tumor growth. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0833DOI Listing

Paclitaxel Induces Immunogenic Cell Death in Ovarian Cancer via TLR4/IKK2/SNARE-Dependent Exocytosis.

Cancer Immunol Res 2020 Apr 30. Epub 2020 Apr 30.

Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.

Emerging evidence shows that the efficacy of chemotherapeutic drugs is reliant on their capability to induce immunogenic cell death (ICD), thus transforming dying tumor cells into antitumor vaccines. We wanted to uncover potential therapeutic strategies that target ovarian cancer by having a better understanding of the standard-of-care chemotherapy treatment. Here, we showed in ovarian cancer that paclitaxel induced ICD-associated damage-associated molecular patterns (DAMP, such as CALR exposure, ATP secretion, and HMGB1 release) and elicited significant antitumor responses in tumor vaccination assays Paclitaxel-induced TLR4 signaling was essential to the release of DAMPs, which led to the activation of NF-κB-mediated CCL2 transcription and IkappaB kinase 2-mediated SNARE-dependent vesicle exocytosis, thus exposing CALR on the cell surface. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0616DOI Listing

Demographic Factors Associated with Toxicity in Patients Treated with Anti-Programmed Cell Death-1 Therapy.

Cancer Immunol Res 2020 Jul 29;8(7):851-855. Epub 2020 Apr 29.

Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Immune checkpoint inhibitors (ICI) are now routinely used in multiple cancers but may induce autoimmune-like side effects known as immune-related adverse events (irAE). Although classical autoimmune diseases have well-known risk factors, including age, gender, and seasonality, the clinical factors that lead to irAEs are not well-defined. To explore these questions, we assessed 455 patients with advanced melanoma treated with ICI at our center and a large pharmacovigilance database (VigiBase). Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334081PMC

Transfer of MicroRNA via Macrophage-Derived Extracellular Vesicles Promotes Proneural-to-Mesenchymal Transition in Glioma Stem Cells.

Cancer Immunol Res 2020 Jul 29;8(7):966-981. Epub 2020 Apr 29.

Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

Proneural-to-mesenchymal transition (PMT) is a common process in glioblastoma (GBM) progression that leads to increased radiotherapy resistance. However, the mechanism underlying PMT is poorly understood. Here, we found that tumor-associated macrophages triggered PMT in glioma stem cells (GSC) via small extracellular vesicles (sEV). Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0759DOI Listing

Tumor Fusion Burden as a Hallmark of Immune Infiltration in Prostate Cancer.

Cancer Immunol Res 2020 Jul 22;8(7):844-850. Epub 2020 Apr 22.

Oncology Biomarker Development, Genentech, Inc., South San Francisco, California.

Prostate cancer is the second leading cause of cancer-related death in men. Despite having a relatively lower tumor mutational burden than most tumor types, multiple gene fusions such as have been characterized and linked to more aggressive disease. Individual tumor samples have been found to contain multiple fusions, and it remains unknown whether these fusions increase tumor immunogenicity. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0568DOI Listing

Genetic Ablation of HLA Class I, Class II, and the T-cell Receptor Enables Allogeneic T Cells to Be Used for Adoptive T-cell Therapy.

Cancer Immunol Res 2020 Jul 22;8(7):926-936. Epub 2020 Apr 22.

Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Adoptive immunotherapy can induce sustained therapeutic effects in some cancers. Antitumor T-cell grafts are often individually prepared from autologous T cells, which requires an intensive workload and increased costs. The quality of the generated T cells can also be variable, which affects the therapy's antitumor efficacy and toxicity. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-18-0508DOI Listing

Mammalian SWI/SNF Complex Genomic Alterations and Immune Checkpoint Blockade in Solid Tumors.

Cancer Immunol Res 2020 Apr 22. Epub 2020 Apr 22.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Prior data have variably implicated the inactivation of the mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) complex with increased tumor sensitivity to immune checkpoint inhibitors (ICI). Herein, we examined the association between mSWI/SNF variants and clinical outcomes to ICIs. We correlated somatic loss-of-function (LOF) variants in a predefined set of mSWI/SNF genes (, and ) with clinical outcomes in patients with cancer treated with systemic ICIs. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0866DOI Listing

Long Noncoding RNAs Control the Modulation of Immune Checkpoint Molecules in Cancer.

Cancer Immunol Res 2020 Jul 22;8(7):937-951. Epub 2020 Apr 22.

Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.

Long noncoding RNAs (lncRNA) that are associated with immune checkpoints have not been identified, and the mechanism by which such lncRNAs might regulate the expression of immune checkpoints is unknown in human cancer. Immune checkpoint-associated lncRNAs (ICP-lncRNA) were identified and validated via a comprehensive bioinformatic analysis of The Cancer Genome Atlas data. These ICP-lncRNAs were involved in key immune response and immune cell receptor signaling pathways. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0696DOI Listing

Characterization of BAY 1905254, an Immune Checkpoint Inhibitor Targeting the Immunoglobulin-Like Domain Containing Receptor 2 (ILDR2).

Cancer Immunol Res 2020 Jul 20;8(7):895-911. Epub 2020 Apr 20.

Immuno-Oncology (Research), Pharmaceuticals Division, Bayer AG, Germany.

The immunoglobulin-like domain containing receptor 2 (ILDR2), a type I transmembrane protein belonging to the B7 family of immunomodulatory receptors, has been described to induce an immunosuppressive effect on T-cell responses. Besides its expression in several nonlymphoid tissue types, we found that ILDR2 was also expressed in fibroblastic reticular cells (FRC) in the stromal part of the lymph node. These immunoregulatory cells were located in the T-cell zone and were essential for the recruitment of naïve T cells and activated dendritic cells to the lymph nodes. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0321DOI Listing

Previous Infection Positively Correlates to the Tumor Incidence Rate of Patients with Cancer.

Cancer Immunol Res 2020 May 17;8(5):580-586. Epub 2020 Apr 17.

Biomedical Science Association, Tokyo, Japan.

We conducted a 7-year case-control study of people ≥30 years of age on the prevalence of influenza, gastroenteritis, hepatitis, and pneumonia infections to indirectly examine whether these infections correlated to malignant cancer formation. Data were extracted from a large medical claims database of a Japanese social health insurance system; the case group included 2,354 people with their first cancer diagnosis in the 7th year of this study, and the control group included 48,395 people with no cancer diagnosis by the 7th year. The yearly prevalence rates of influenza, gastroenteritis, hepatitis, and pneumonia infections increased throughout the study period. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0510DOI Listing

SHP-2 and PD-L1 Inhibition Combined with Radiotherapy Enhances Systemic Antitumor Effects in an Anti-PD-1-Resistant Model of Non-Small Cell Lung Cancer.

Cancer Immunol Res 2020 Jul 16;8(7):883-894. Epub 2020 Apr 16.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Immune checkpoint inhibitors, such as anti-PD-1/PD-L1, have emerged as promising therapies for advanced non-small cell lung cancer (NSCLC). However, approximately 80% of patients do not respond to immunotherapy given alone because of intrinsic or acquired resistance. Radiotherapy (XRT) can overcome PD-1 resistance and improve treatment outcomes, but its efficacy remains suboptimal. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0744DOI Listing

Vaccination against Nonmutated Neoantigens Induced in Recurrent and Future Tumors.

Cancer Immunol Res 2020 Jul 15;8(7):856-868. Epub 2020 Apr 15.

Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida.

Vaccination of patients against neoantigens expressed in concurrent tumors, recurrent tumors, or tumors developing in individuals at risk of cancer is posing major challenges in terms of which antigens to target and is limited to patients expressing neoantigens in their tumors. Here, we describe a vaccination strategy against antigens that were induced in tumor cells by downregulation of the peptide transporter associated with antigen processing (TAP). Vaccination against TAP downregulation-induced antigens was more effective than vaccination against mutation-derived neoantigens, was devoid of measurable toxicity, and inhibited the growth of concurrent and future tumors in models of recurrence and premalignant disease. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-20-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339786PMC

Dual Relief of T-lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies.

Cancer Immunol Res 2020 Jul 15;8(7):869-882. Epub 2020 Apr 15.

Cancer Research Center of Toulouse, INSERM UMR 1037, Toulouse, France.

Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8 T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0855DOI Listing

CD137/OX40 Bispecific Antibody Induces Potent Antitumor Activity that Is Dependent on Target Coengagement.

Cancer Immunol Res 2020 Jun 9;8(6):781-793. Epub 2020 Apr 9.

F-star Therapeutics Ltd., Cambridge, United Kingdom.

Following the success of immune checkpoint blockade therapy against cancer, agonistic antibodies targeting T-cell costimulatory pathways are in clinical trials. The TNF superfamily of receptors (TNFRSF) members CD137 and OX40 are costimulatory receptors that stimulate T-cell proliferation and activation upon interaction with their cognate ligands. Activating CD137 and OX40 with agonistic mAbs stimulates the immune system due to their broad expression on CD4 and CD8 T cells and natural killer cells and has antitumor effects in preclinical models. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0798DOI Listing

CD226CD8 T Cells Are a Prerequisite for Anti-TIGIT Immunotherapy.

Cancer Immunol Res 2020 Jul 7;8(7):912-925. Epub 2020 Apr 7.

Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, South Korea.

Clinical trials are evaluating the efficacy of anti-TIGIT for use as single-agent therapy or in combination with programmed death 1 (PD-1)/programmed death-ligand 1 blockade. How and whether a TIGIT blockade will synergize with immunotherapies is not clear. Here, we show that CD226CD8 T cells accumulate at the tumor site and have an exhausted phenotype with impaired functionality. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0877DOI Listing

Verteporfin Inhibits PD-L1 through Autophagy and the STAT1-IRF1-TRIM28 Signaling Axis, Exerting Antitumor Efficacy.

Cancer Immunol Res 2020 Jul 7;8(7):952-965. Epub 2020 Apr 7.

Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Programmed cell death 1 ligand 1 (PD-L1) is a key driver of tumor-mediated immune suppression, and targeting it with antibodies can induce therapeutic responses. Given the costs and associated toxicity of PD-L1 blockade, alternative therapeutic strategies are needed. Using reverse-phase protein arrays to assess drugs in use or likely to enter trials, we performed a candidate drug screen for inhibitors of PD-L1 expression and identified verteporfin as a possible small-molecule inhibitor. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0159DOI Listing

Immune Escape during Breast Tumor Progression.

Cancer Immunol Res 2020 Apr;8(4):422-427

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Immunotherapy using checkpoint inhibitors is one of the most promising current cancer treatment strategies. However, in breast cancer, its success has been limited to a subset of patients with triple-negative disease, whose durability of observed responses remain unclear. The lack of detailed understanding of breast tumor immune evasion mechanisms and the treatment of patients with highly heterogeneous metastatic disease contribute to these disappointing results. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138346PMC

CSF1R Is Required for Differentiation and Migration of Langerhans Cells and Langerhans Cell Histiocytosis.

Cancer Immunol Res 2020 Jun 1;8(6):829-841. Epub 2020 Apr 1.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by tissue accumulation of CD1aCD207 LCH cells. In LCH, somatic mutations of the gene have been detected in tissue LCH cells, bone marrow CD34 hematopoietic stem cells, circulating CD14 monocytes, and BDCA1 myeloid dendritic cells (DC). Targeting in clonal Langerhans cells (LC) and their precursors is a potential treatment option for patients whose tumors have the mutation. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0232DOI Listing

Anti-VEGF Treatment Enhances CD8 T-cell Antitumor Activity by Amplifying Hypoxia.

Cancer Immunol Res 2020 Jun 1;8(6):806-818. Epub 2020 Apr 1.

Department of Molecular Oncology, Genentech, Inc., South San Francisco, California.

Antiangiogenic therapies that target the VEGF pathway have been used clinically to combat cancer for over a decade. Beyond having a direct impact on blood vessel development and tumor perfusion, accumulating evidence indicates that these agents also affect antitumor immune responses. Numerous clinical trials combining antiangiogenic drugs with immunotherapies for the treatment of cancer are ongoing, but a mechanistic understanding of how disruption of tumor angiogenesis may impact immunity is not fully discerned. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0360DOI Listing

Quantification of Early-Stage Myeloid-Derived Suppressor Cells in Cancer Requires Excluding Basophils.

Cancer Immunol Res 2020 Jun 1;8(6):819-828. Epub 2020 Apr 1.

Department of Internal Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Myeloid derived suppressor cells (MDSC) are a heterogeneous group of immature cells that accumulate in the peripheral blood and tumor microenvironment and are barriers to cancer therapy. MDSCs serve as prognostic biomarkers and are targets for therapy. On the basis of surface markers, three subsets of MDSCs have been defined in humans: granulocytic, monocytic, and early stage (e-MDSC). Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269807PMC

Human NKp44 Group 3 Innate Lymphoid Cells Associate with Tumor-Associated Tertiary Lymphoid Structures in Colorectal Cancer.

Cancer Immunol Res 2020 Jun 30;8(6):724-731. Epub 2020 Mar 30.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

Innate lymphoid cells (ILC) are responsible for mucosal tissue homeostasis and are involved in the progression and suppression of several types of cancer. However, the effects of ILCs on colorectal cancer are poorly understood. We characterized human ILCs in normal colon and colorectal cancer tissue, investigating their role in the tumor immune microenvironment. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0775DOI Listing

Histone Deacetylase Inhibitors and IL21 Cooperate to Reprogram Human Effector CD8 T Cells to Memory T Cells.

Cancer Immunol Res 2020 Jun 25;8(6):794-805. Epub 2020 Mar 25.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Clinical response rates after adoptive cell therapy (ACT) are highly correlated with persistence of the infused T cells. However, antigen-specific T cells found in tumor sites are often well-differentiated effector cells with limited persistence. Central memory CD8 T cells, capable of self-renewal, represent desirable ACT products. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269845PMC

Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells.

Cancer Immunol Res 2020 Jun 25;8(6):732-742. Epub 2020 Mar 25.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Although clinical responses with CD19-targeting chimeric antigen receptor (CAR) T-cell treatment have been observed in patients with certain hematologic malignancies, high rates of disease relapse highlight the necessity to understand and improve mechanisms of CAR T-cell failure. Because T-cell dysfunction is thought to contribute to CAR T-cell treatment failure, understanding what mechanisms drive T cells into this dysfunctional state may aid optimal design of efficacious CAR T cells. Dysfunctional CAR T cells have been characterized as having upregulated inhibitory receptors and decreased cytolytic capabilities. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269815PMC

Optimization of T-cell Receptor-Modified T Cells for Cancer Therapy.

Cancer Immunol Res 2020 Jun 24;8(6):743-755. Epub 2020 Mar 24.

Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York.

T-cell receptor (TCR)-modified T-cell gene therapy can target a variety of extracellular and intracellular tumor-associated antigens, yet has had little clinical success. A potential explanation for limited antitumor efficacy is a lack of T-cell activation We postulated that expression of proinflammatory cytokines in TCR-modified T cells would activate T cells and enhance antitumor efficacy. We demonstrate that expression of interleukin 18 (IL18) in tumor-directed TCR-modified T cells provides a superior proinflammatory signal than expression of interleukin 12 (IL12). Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269835PMC

Inhibition of MICA and MICB Shedding Elicits NK-Cell-Mediated Immunity against Tumors Resistant to Cytotoxic T Cells.

Cancer Immunol Res 2020 Jun 24;8(6):769-780. Epub 2020 Mar 24.

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Resistance to cytotoxic T cells is frequently mediated by loss of MHC class I expression or IFNγ signaling in tumor cells, such as mutations of or genes. Natural killer (NK) cells could potentially target such resistant tumors, but suitable NK-cell-based strategies remain to be developed. We hypothesized that such tumors could be targeted by NK cells if sufficient activating signals were provided. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269842PMC

Donor Lymphocyte-Derived Natural Killer Cells Control MHC Class I-Negative Melanoma.

Cancer Immunol Res 2020 Jun 24;8(6):756-768. Epub 2020 Mar 24.

Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.

Natural killer (NK) cells provide a natural defense against MHC-I-negative tumors, such as melanoma. Donor lymphocyte infusion (DLI) containing NK cells, a form of adoptive immunotherapy used after allogenic bone marrow transplantation (allo-BMT), promotes antitumor immune responses but is often associated with life-threatening complications such as graft-versus-host disease (GvHD). Here, we showed that without prior allo-BMT, DLI provoked melanoma control associated with the infiltration and persistence of the transferred NK cells. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0666DOI Listing

Enhanced Immunogenicity of Mitochondrial-Localized Proteins in Cancer Cells.

Cancer Immunol Res 2020 May 23;8(5):685-697. Epub 2020 Mar 23.

MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

Epitopes derived from mutated cancer proteins elicit strong antitumor T-cell responses that correlate with clinical efficacy in a proportion of patients. However, it remains unclear whether the subcellular localization of mutated proteins influences the efficiency of T-cell priming. To address this question, we compared the immunogenicity of NY-ESO-1 and OVA localized either in the cytosol or in mitochondria. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0467DOI Listing

Identification of the Targets of T-cell Receptor Therapeutic Agents and Cells by Use of a High-Throughput Genetic Platform.

Cancer Immunol Res 2020 May 17;8(5):672-684. Epub 2020 Mar 17.

Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York

T-cell receptor (TCR)-based therapeutic cells and agents have emerged as a new class of effective cancer therapies. These therapies work on cells that express intracellular cancer-associated proteins by targeting peptides displayed on MHC receptors. However, cross-reactivities of these agents to off-target cells and tissues have resulted in serious, sometimes fatal, adverse events. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310334PMC

A PSMA-Targeting CD3 Bispecific Antibody Induces Antitumor Responses that Are Enhanced by 4-1BB Costimulation.

Cancer Immunol Res 2020 May 17;8(5):596-608. Epub 2020 Mar 17.

Regeneron Pharmaceuticals, Inc., Tarrytown, New York.

Patients with hematologic cancers have improved outcomes after treatment with bispecific antibodies that bind to CD3 on T cells and that redirect T cells toward cancer cells. However, clinical benefit against solid tumors remains to be shown. We made a bispecific antibody that targets both the common prostate tumor-specific antigen PSMA and CD3 (PMSAxCD3) and provide evidence for tumor inhibition in several preclinical solid tumor models. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0518DOI Listing

Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8 T Cells within Polyomavirus-Driven Merkel Cell Carcinomas.

Cancer Immunol Res 2020 May 16;8(5):648-659. Epub 2020 Mar 16.

Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington.

Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AA). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag-specific T cells. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196523PMC

IL1α Antagonizes IL1β and Promotes Adaptive Immune Rejection of Malignant Tumors.

Cancer Immunol Res 2020 May 11;8(5):660-671. Epub 2020 Mar 11.

Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

We assessed the contribution of IL1 signaling molecules to malignant tumor growth using IL1β, IL1α, and IL1R1 mice. Tumors grew progressively in IL1R and IL1α mice but were often absent in IL1β mice. This was observed whether tumors were implanted intradermally or injected intravenously and was true across multiple distinct tumor lineages. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0552DOI Listing

Single-Cell Immune Competency Signatures Associate with Survival in Phase II GVAX and CRS-207 Randomized Studies in Patients with Metastatic Pancreatic Cancer.

Cancer Immunol Res 2020 May 4;8(5):609-617. Epub 2020 Mar 4.

Rapt Therapeutics, Inc., South San Francisco, California.

The identification of biomarkers for patient stratification is fundamental to precision medicine efforts in oncology. Here, we identified two baseline, circulating immune cell subsets associated with overall survival in patients with metastatic pancreatic cancer who were enrolled in two phase II randomized studies of GVAX pancreas and CRS-207 immunotherapy. Single-cell mass cytometry was used to simultaneously measure 38 cell surface or intracellular markers in peripheral blood mononuclear cells obtained from a phase IIa patient subcohort ( = 38). Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0650DOI Listing

Interferon-Induced IDO1 Mediates Radiation Resistance and Is a Therapeutic Target in Colorectal Cancer.

Cancer Immunol Res 2020 Apr 3;8(4):451-464. Epub 2020 Mar 3.

Inflammatory Bowel Diseases Center and the Division of Gastroenterology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri.

Colorectal cancer is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor colorectal cancer clinical outcomes but is understudied as a potential treatment target. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123802PMC

Deciphering the Immunomodulatory Capacity of Oncolytic Vaccinia Virus to Enhance the Immune Response to Breast Cancer.

Cancer Immunol Res 2020 May 3;8(5):618-631. Epub 2020 Mar 3.

Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, Alberta, Canada.

Vaccinia virus (VACV) is a double-stranded DNA virus that devotes a large portion of its 200 kbp genome to suppressing and manipulating the immune response of its host. Here, we investigated how targeted removal of immunomodulatory genes from the VACV genome impacted immune cells in the tumor microenvironment with the intention of improving the therapeutic efficacy of VACV in breast cancer. We performed a head-to-head comparison of six mutant oncolytic VACVs, each harboring deletions in genes that modulate different cellular pathways, such as nucleotide metabolism, apoptosis, inflammation, and chemokine and interferon signaling. Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0703DOI Listing

Intratumoral Delivery of a PD-1-Blocking scFv Encoded in Oncolytic HSV-1 Promotes Antitumor Immunity and Synergizes with TIGIT Blockade.

Cancer Immunol Res 2020 May 3;8(5):632-647. Epub 2020 Mar 3.

State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China.

Oncolytic virotherapy can lead to systemic antitumor immunity, but the therapeutic potential of oncolytic viruses in humans is limited due to their insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). Here, we showed that locoregional oncolytic virotherapy upregulated the expression of PD-L1 in the TME, which was mediated by virus-induced type I and type II IFNs. To explore PD-1/PD-L1 signaling as a direct target in tumor tissue, we developed a novel immunotherapeutic herpes simplex virus (HSV), OVH-aMPD-1, that expressed a single-chain variable fragment (scFv) against PD-1 (aMPD-1 scFv). Read More

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http://dx.doi.org/10.1158/2326-6066.CIR-19-0628DOI Listing