Publications by authors named "Fumito Ito"

30 Publications

  • Page 1 of 1

T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors.

Nat Commun 2021 03 3;12(1):1402. Epub 2021 Mar 3.

Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1CD8 T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8 T cells. Furthermore, an increase in the frequency of the CX3CR1 subset in circulating CD8 T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy.
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http://dx.doi.org/10.1038/s41467-021-21619-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930182PMC
March 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 Otolaryngology, Stanford University School of Medicine, Stanford, California, 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

Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s.

Nat Commun 2020 10 27;11(1):5415. Epub 2020 Oct 27.

Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

The ability of cancer cells to ensure T-cell exclusion from the tumor microenvironment is a significant mechanism of resistance to anti-PD-1/PD-L1 therapy. Evidence indicates crucial roles of Batf3-dependent conventional type-1 dendritic cells (cDC1s) for inducing antitumor T-cell immunity; however, strategies to maximize cDC1 engagement remain elusive. Here, using multiple orthotopic tumor mouse models resistant to anti-PD-L1-therapy, we are testing the hypothesis that in situ induction and activation of tumor-residing cDC1s overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1 Slamf6 CD8 T cells, triggers regression not only of primary, but also untreated distant tumors, and renders tumors responsive to anti-PD-L1 therapy. Furthermore, serial in situ immunomodulation (ISIM) reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, and establishes tumor-specific immunological memory. These findings provide new insights into cDC1 biology as a critical determinant to overcome mechanisms of intratumoral T-cell exclusion.
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http://dx.doi.org/10.1038/s41467-020-19192-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592056PMC
October 2020

A Critical Role of CD40 and CD70 Signaling in Conventional Type 1 Dendritic Cells in Expansion and Antitumor Efficacy of Adoptively Transferred Tumor-Specific T Cells.

J Immunol 2020 10 26;205(7):1867-1877. Epub 2020 Aug 26.

Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263;

In vivo expansion of adoptively transferred CD8 T cells is a critical determinant of successful adoptive T cell therapy. Emerging evidence indicates Batf3-dependent conventional type 1 dendritic cells (cDC1s) rarely found within the tumor myeloid compartment are crucial for effector T cell recruitment to the tumor microenvironment. However, the role of cDC1s in expansion of tumor-specific CD8 T cells remains unclear. In this article, we addressed the role of cDC1s and their costimulatory molecules, CD40, CD70, and CD80/CD86, in expansion and antitumor efficacy of adoptively transferred in vitro-primed CD8 T cells recognizing nonmutated tumor-associated self-antigens. We found that TLR/CD40-mediated expansion and antitumor efficacy of adoptively transferred tumor-specific CD8 T cells were abrogated in Batf3 mice. Further mechanistic studies using mixed bone marrow chimeric mice identified that CD40 and CD70 but not CD80/CD86 signaling in cDC1s played a critical role in expansion and antitumor efficacy of adoptively transferred CD8 T cells. Moreover, induction and activation of cDC1s by administration of FMS-like tyrosine kinase 3 ligand (Flt3L) and TLR/CD40 agonists augmented expansion of adoptively transferred CD8 T cells, delayed tumor growth, and improved survival. These findings reveal a key role for CD40 and CD70 signaling in cDC1s and have major implications for the design of new vaccination strategies with adoptive T cell therapy.
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http://dx.doi.org/10.4049/jimmunol.2000347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511447PMC
October 2020

CX3CR1-CD8+ T cells are critical in antitumor efficacy but functionally suppressed in the tumor microenvironment.

JCI Insight 2020 04 23;5(8). Epub 2020 Apr 23.

Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

Although blockade of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint has revolutionized cancer treatment, how it works on tumor-infiltrating CD8+ T cells recognizing the same antigen at various differentiation stages remains elusive. Here, we found that the chemokine receptor CX3CR1 identified 3 distinct differentiation states of intratumor CD8+ T cell subsets. Adoptively transferred antigen-specific CX3CR1-CD8+ T cells generated phenotypically and functionally distinct CX3CR1int and CX3CR1hi subsets in the periphery. Notably, expression of coinhibitory receptors and T cell factor 1 (Tcf1) inversely correlated with the degree of T cell differentiation defined by CX3CR1. Despite lower expression of coinhibitory receptors and potent cytolytic activity, in vivo depletion of the CX3CR1hi subset did not alter the antitumor efficacy of adoptively transferred CD8+ T cells. Furthermore, differentiated CX3CR1int and CX3CR1hi subsets were impaired in their ability to undergo proliferation upon restimulation and had no impact on established tumors upon second adoptive transfer compared with the CX3CR1- subset that remained effective. Accordingly, anti-PD-L1 therapy preferentially rescued proliferation and cytokine production of the CX3CR1- subset and enhanced antitumor efficacy of adoptively transferred CD8+ T cells. These findings provide a better understanding of the phenotypic and functional heterogeneity of tumor-infiltrating CD8+ T cells and can be exploited to develop more effective immunotherapy.
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http://dx.doi.org/10.1172/jci.insight.133920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205436PMC
April 2020

thermal ablation augments antitumor efficacy of adoptive T cell therapy.

Int J Hyperthermia 2019 11;36(sup1):22-36

Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

The aim of this study is to investigate whether radiofrequency ablation (RFA) improves the efficacy of adoptive T cell immunotherapy in preclinical mouse cancer models. Mice implanted subcutaneously () with syngeneic colon adenocarcinoma or melanoma were treated with sub-curative RFA (90 °C, 1 min). Trafficking of T cells to lymph nodes (LN) or tumors was quantified by homing assays and intravital microscopy (IVM) after sham procedure or RFA. Expression of trafficking molecules (CCL21 and intercellular adhesion molecule-1 [ICAM-1]) on high endothelial venules (HEV) in LN and tumor vessels was evaluated by immunofluorescence microscopy. Tumor-bearing mice were pretreated with RFA to investigate the therapeutic benefit when combined with adoptive transfer of -activated tumor-specific CD8 T cells. RFA increased trafficking of naïve CD8 T cells to tumor-draining LN (TdLN). A corresponding increase in expression of ICAM-1 and CCL21 was detected on HEV in TdLN but not in contralateral (c)LN. IVM revealed that RFA substantially enhanced secondary firm arrest of lymphocytes selectively in HEV in TdLN. Furthermore, strong induction of ICAM-1 in tumor vessels was associated with significantly augmented trafficking of adoptively transferred -activated CD8 T cells to tumors after RFA. Finally, preconditioning tumors with RFA augmented CD8 T cell-mediated apoptosis of tumor targets and delayed growth of established tumors when combined with adoptive T cell transfer immunotherapy. These studies suggest that in addition to its role as a palliative therapeutic modality, RFA may have clinical potential as an immune-adjuvant therapy by augmenting the efficacy of adoptive T cell therapy.
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http://dx.doi.org/10.1080/02656736.2019.1653500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897324PMC
November 2019

Induced Pluripotent Stem Cell-Derived T Cells for Cancer Immunotherapy.

Surg Oncol Clin N Am 2019 07 10;28(3):489-504. Epub 2019 Apr 10.

Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, CCC-539, Buffalo, NY 14263, USA; Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA. Electronic address:

Adoptive T cell therapy for solid malignancies is limited because obtaining sufficient numbers of less-differentiated tumor-specific T cells is difficult. This roadblock can be theoretically overcome by the use of induced pluripotent stem cells (iPSCs), which self-renew and provide unlimited numbers of autologous less-differentiated T cells. iPSCs can generate less-differentiated antigen-specific T cells that harbor long telomeres and increased proliferative capacity, and exhibit potent antitumor efficacy. Although this strategy holds great promise for adoptive T cell therapy, highly reproducible and robust differentiation protocols are required before the translation of iPSC technology into the clinical setting.
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http://dx.doi.org/10.1016/j.soc.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516087PMC
July 2019

Low DMT1 Expression Associates With Increased Oxidative Phosphorylation and Early Recurrence in Hepatocellular Carcinoma.

J Surg Res 2019 02;234:343-352

Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York; Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York; Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, New York. Electronic address:

Background: Despite a high rate of recurrences, long-term survival can be achieved after the resection of hepatocellular carcinoma (HCC) with effective local treatment. Discovery of adverse prognostic variables to identify patients with high risk of recurrence could improve the management of HCC. Accumulating evidence showing a link between carcinogenesis and increased expression of iron import proteins and intracellular iron prompted us to investigate a role of divalent metal-ion transporter-1 (DMT1) that binds and regulates a variety of divalent metals in HCC.

Materials And Methods: Clinical and gene expression data from RNA seq in 369 HCC patients were obtained from The Cancer Genome Atlas. Disease-free survival was compared between DMT1 high- and low-expressing tumors, and gene set enrichment analysis was conducted.

Results: Patients with lower expression of DMT1 exhibited significantly worse disease-free survival compared with the DMT1 high group (P = 0.044), notably in advanced-stage patients (P = 0.008). DMT1 expression did not differ in etiologies, stages, and differentiation status of HCC. Interestingly, DMT1 expression levels inversely associated with cellular respiratory function in HCC. Furthermore, gene set enrichment analysis revealed that metabolism-related gene sets such as glycolysis, oxidative phosphorylation, and reactive oxygen species pathway were significantly enriched in the DMT1 low-expressing HCC.

Conclusions: Low DMT1 expression associates with increased oxidative phosphorylation as well as glycolysis and identifies early recurrence in HCC patients after surgical treatment.
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http://dx.doi.org/10.1016/j.jss.2018.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291835PMC
February 2019

Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System.

Cell Rep 2018 03;22(12):3175-3190

Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Center for Cell-Based Therapy, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:

Induced pluripotent stem cell (iPSC)-derived T cells may provide future therapies for cancer patients, but those generated by current methods, such as the OP9/DLL1 system, have shown abnormalities that pose major barriers for clinical translation. Our data indicate that these iPSC-derived CD8 single-positive T cells are more like CD4CD8 double-positive T cells than mature naive T cells because they display phenotypic markers of developmental arrest and an innate-like phenotype after stimulation. We developed a 3D thymic culture system to avoid these aberrant developmental fates, generating a homogeneous subset of CD8αβ antigen-specific T cells, designated iPSC-derived thymic emigrants (iTEs). iTEs exhibit phenotypic and functional similarities to naive T cells both in vitro and in vivo, including the capacity for expansion, memory formation, and tumor suppression. These data illustrate the limitations of current methods and provide a tool to develop the next generation of iPSC-based antigen-specific immunotherapies.
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http://dx.doi.org/10.1016/j.celrep.2018.02.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930030PMC
March 2018

Emerging role of RNA binding protein UNR/CSDE1 in melanoma.

J Xiangya Med 2017 May 5;2. Epub 2017 May 5.

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.

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http://dx.doi.org/10.21037/jxym.2017.03.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100785PMC
May 2017

Generation of Induced Pluripotent Stem Cells from Human Melanoma Tumor-infiltrating Lymphocytes.

J Vis Exp 2016 11 11(117). Epub 2016 Nov 11.

Center for Immunotherapy, Roswell Park Cancer Institute; Department of Surgical Oncology, Roswell Park Cancer Institute;

Adoptive transfer of ex vivo expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate durable and complete responses in significant subsets of patients with metastatic melanoma. Major obstacles of this approach are the reduced viability of transferred T cells, caused by telomere shortening, and the limited number of TILs obtained from patients. Less-differentiated T cells with long telomeres would be an ideal T cell subset for adoptive T cell therapy;however, generating large numbers of these less-differentiated T cells is problematic. This limitation of adoptive T cell therapy can be theoretically overcome by using induced pluripotent stem cells (iPSCs) that self-renew, maintain pluripotency, have elongated telomeres, and provide an unlimited source of autologous T cells for immunotherapy. Here, we present a protocol to generate iPSCs using Sendai virus vectors for the transduction of reprogramming factors into TILs. This protocol generates fully reprogrammed, vector-free clones. These TIL-derived iPSCs might be able to generate less-differentiated patient- and tumor-specific T cells for adoptive T cell therapy.
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http://dx.doi.org/10.3791/54375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226217PMC
November 2016

Adoptive Transfer of CD8+ T Cells Generated from Induced Pluripotent Stem Cells Triggers Regressions of Large Tumors Along with Immunological Memory.

Cancer Res 2016 06 12;76(12):3473-83. Epub 2016 Apr 12.

Department of Surgery, University of Michigan, Ann Arbor, Michigan. Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York. Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York.

Current approaches to adoptive T-cell therapy are limited by the difficulty of obtaining sufficient numbers of T cells against targeted antigens with useful in vivo characteristics. Theoretically, this limitation could be overcome by using induced pluripotent stem cells (iPSC) that could provide an unlimited source of autologous T cells. However, the therapeutic efficacy of iPSC-derived regenerated T cells remains to be demonstrated. Here, we report the first successful reprogramming of T-cell receptor (TCR) transgenic CD8(+) T cells into pluripotency. As part of the work, we established a syngeneic mouse model for evaluating in vitro and in vivo antitumor reactivity of regenerated T cells from iPSCs bearing a rearranged TCR of known antigen specificity. Stably TCR retained T-cell-derived iPSCs differentiated into CD4(+)CD8(+) T cells that expressed CD3 and the desired TCR in vitro Stimulation of iPSC-derived CD4(+)CD8(+) T cells with the cognate antigen in the presence of IL7 and IL15 followed by expansion with IL2, IL7, and IL15 generated large numbers of less-differentiated CD8(+) T cells with antigen-specific potent cytokine production and cytolytic capacity. Furthermore, adoptively transferred iPSC-derived CD8(+) T cells escaped immune rejection, mediated effective regression of large tumors, improved survival, and established antigen-specific immunological memory. Our findings illustrate the translational potential of iPSCs to provide an unlimited number of phenotypically defined, functional, and expandable autologous antigen-specific T cells with the characteristics needed to enable in vivo effectiveness. Cancer Res; 76(12); 3473-83. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911287PMC
June 2016

Reprogramming of Melanoma Tumor-Infiltrating Lymphocytes to Induced Pluripotent Stem Cells.

Stem Cells Int 2016 28;2016:8394960. Epub 2015 Dec 28.

Department of Surgery, University of Michigan, 1500 E Medical Center Drive, 3410 CC, Ann Arbor, MI 48109-5932, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2200, USA.

Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients hold great promise for autologous cell therapies. One of the possible applications of iPSCs is to use them as a cell source for producing autologous lymphocytes for cell-based therapy against cancer. Tumor-infiltrating lymphocytes (TILs) that express programmed cell death protein-1 (PD-1) are tumor-reactive T cells, and adoptive cell therapy with autologous TILs has been found to achieve durable complete response in selected patients with metastatic melanoma. Here, we describe the derivation of human iPSCs from melanoma TILs expressing high level of PD-1 by Sendai virus-mediated transduction of the four transcription factors, OCT3/4, SOX2, KLF4, and c-MYC. TIL-derived iPSCs display embryonic stem cell-like morphology, have normal karyotype, express stem cell-specific surface antigens and pluripotency-associated transcription factors, and have the capacity to differentiate in vitro and in vivo. A wide variety of T cell receptor gene rearrangement patterns in TIL-derived iPSCs confirmed the heterogeneity of T cells infiltrating melanomas. The ability to reprogram TILs containing patient-specific tumor-reactive repertoire might allow the generation of patient- and tumor-specific polyclonal T cells for cancer immunotherapy.
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http://dx.doi.org/10.1155/2016/8394960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707343PMC
April 2016

Pre-resectional Radiofrequency Ablation as a Neoadjuvant Tumor Vaccine.

J Vaccines Vaccin 2016 Apr 9;7(2). Epub 2016 Mar 9.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA.

A lack of effective immune response against cancer is one of the major risk factors for developing local recurrence and distant metastases after curative resectional surgery. Prior studies revealed that systemic antitumor immunity is elicited by radiofrequency ablation (RFA) of tumor lesions, which is mainly considered a palliative procedure for unresectable tumors or for inoperable patients. Recently, we discovered an oncological benefit that depends on the adaptive arm of the antitumor immune response when RFA is performed in a neoadjuvant setting prior to surgical resection in preclinical murine models.
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http://dx.doi.org/10.4172/2157-7560.1000310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606234PMC
April 2016

Immune Adjuvant Activity of Pre-Resectional Radiofrequency Ablation Protects against Local and Systemic Recurrence in Aggressive Murine Colorectal Cancer.

PLoS One 2015 23;10(11):e0143370. Epub 2015 Nov 23.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.

Purpose: While surgical resection is a cornerstone of cancer treatment, local and distant recurrences continue to adversely affect outcome in a significant proportion of patients. Evidence that an alternative debulking strategy involving radiofrequency ablation (RFA) induces antitumor immunity prompted the current investigation of the efficacy of performing RFA prior to surgical resection (pre-resectional RFA) in a preclinical mouse model.

Experimental Design: Therapeutic efficacy and systemic immune responses were assessed following pre-resectional RFA treatment of murine CT26 colon adenocarcinoma.

Results: Treatment with pre-resectional RFA significantly delayed tumor growth and improved overall survival compared to sham surgery, RFA, or resection alone. Mice in the pre-resectional RFA group that achieved a complete response demonstrated durable antitumor immunity upon tumor re-challenge. Failure to achieve a therapeutic benefit in immunodeficient mice confirmed that tumor control by pre-resectional RFA depends on an intact adaptive immune response rather than changes in physical parameters that make ablated tumors more amenable to a complete surgical excision. RFA causes a marked increase in intratumoral CD8+ T lymphocyte infiltration, thus substantially enhancing the ratio of CD8+ effector T cells: FoxP3+ regulatory T cells. Importantly, pre-resectional RFA significantly increases the number of antigen-specific CD8+ T cells within the tumor microenvironment and tumor-draining lymph node but had no impact on infiltration by myeloid-derived suppressor cells, M1 macrophages or M2 macrophages at tumor sites or in peripheral lymphoid organs (i.e., spleen). Finally, pre-resectional RFA of primary tumors delayed growth of distant tumors through a mechanism that depends on systemic CD8+ T cell-mediated antitumor immunity.

Conclusion: Improved survival and antitumor systemic immunity elicited by pre-resectional RFA support the translational potential of this neoadjuvant treatment for cancer patients with high-risk of local and systemic recurrence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143370PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657935PMC
June 2016

Antitumor effector B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10.

Eur J Immunol 2015 Apr 21;45(4):999-1009. Epub 2015 Jan 21.

Department of Surgery, University of Michigan, , Ann Arbor, MI, USA; Hubei Province Stem Cell Research and Appling Center, Institute of Hematology, , Union Hospital, , Tongji Medical College, , Huazhong University of Science and Technology, Wuhan, China.

We have previously reported that adoptive transfer of tumor-draining lymph node (TDLN) B cells confers tumor regression in a spontaneous pulmonary metastasis mouse model of breast cancer. In this study, we identified IL-10-producing cells within these B cells, and found that IL-10 removal, either by using IL-10(-/-) TDLN B cells or by systemic neutralization of IL-10, significantly augmented the therapeutic efficacy of adoptively transferred TDLN B cells. Depletion of IL-10 in B-cell adoptive transfers significantly increased CTLs and B-cell activity of PBMCs and splenic cells in the recipient. Activated TDLN B cells express Fas ligand, which was further enhanced by coculture of these TDLN B cells with 4T1 tumor cells. Effector B cells killed tumor cells directly in vitro in an antigen specific and Fas ligand-dependent manner. Trafficking of TDLN B cells in vivo suggested that they were recruited to the tumor and lung as well as secondary lymphoid organs. These findings further define the biological function of antitumor effector B cells, which may offer alternative cellular therapies to cancer.
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http://dx.doi.org/10.1002/eji.201444625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414939PMC
April 2015

Cancer immunotherapy: current status and future directions.

Surg Oncol Clin N Am 2013 Oct 26;22(4):765-83. Epub 2013 Jul 26.

Department of Surgery, University of Michigan Health System, 3410 Cancer Center/5932, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5932, USA.

Better understanding of the underlying principles of tumor biology and immunology, enhanced by recent insights into the mechanisms of immune recognition, regulation, and tumor escape has provided new approaches for cancer immunotherapy. This article reviews the current status and future directions of cancer immunotherapy, with a focus on the recent encouraging results from immune-modulating antibodies and adoptive cell therapy.
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http://dx.doi.org/10.1016/j.soc.2013.06.005DOI Listing
October 2013

Approach to assessing the walking motion of elderly males based on kinetic parameters of young males.

Rejuvenation Res 2012 Apr;15(2):198-200

Department of Mechanical Engineering and Intelligent Systems, The University of Electro-Communications, Tokyo, Japan.

The objectives of this study were to explore a method of evaluating the walking motion of elderly males using mainly kinetic parameters and to determine how to maintain their level of walking motion to equal that of the young. We employed the coefficient of variation (CV) (=standard deviation[SD]/MEAN * 100), z-score, and weighted z-score (WZ) (=z-score/CV) and examined the relationship between the WZ of each parameter and age by regression analysis. Finally, we used the regression line to estimate "gait age" and determined the critical factors of gait decay in elderly individuals.
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http://dx.doi.org/10.1089/rej.2011.1283DOI Listing
April 2012

Water: a simple solution for tumor spillage.

Ann Surg Oncol 2011 Aug 8;18(8):2357-63. Epub 2011 Feb 8.

Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.

Background: Although often proposed as a means to reduce the harmful consequences of tumor spill, water lavage has yet to be systematically evaluated in relevant in vitro and in vivo models. This study evaluates the mechanisms and utility of a single water lavage to improve the sequelae of tumor spill during laparotomy.

Methods: Murine colorectal tumor cell susceptibility to water-induced osmotic lysis was characterized in vitro. A reproducible model of tumor spill was established to recapitulate water or saline lavage during laparotomy. Analyses of tumor volumes calculated from noninvasive imaging were performed. The tumor volumes and survival of mice treated with water, normal saline, or sham laparotomy were assessed.

Results: Significant osmotic lysis of cultured murine colorectal cancer cells was observed after a brief exposure to water. Compared to saline or sham laparotomy, water lavage demonstrated superior clinical outcomes with a decrease in tumor burden and concomitant improvement in survival.

Conclusions: The use of water lavage during oncologic surgeries to reduce the sequelae of tumor spill is justified and strongly supported by our study. Data from our study raise several concerns regarding the mechanisms and efficacy of saline lavage. Clinically, the use of water lavage during laparotomy would be anticipated to reduce peritoneal disease burden with minimal toxicity or cost.
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http://dx.doi.org/10.1245/s10434-011-1588-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778406PMC
August 2011

Hilar cholangiocarcinoma: current management.

Ann Surg 2009 Aug;250(2):210-8

University of Wisconsin, Madison, WI 53792-7375, USA.

Objective: To review the literature with regard to outcome of surgical management for hilar cholangiocarcinoma (Klatskin tumor).

Background: Hilar cholangiocarcinoma is a rare tumor with a poor prognosis. Surgical resection provides the only possibility for cure. Advances in hepatobiliary imaging and surgical strategies to treat this disease have resulted in improved postoperative outcomes.

Methods: We performed a review of the English literature on hilar cholangiocarcinoma from 1990 to 2007. This review included preoperative evaluation, surgical techniques, issues and controversies in management, prognostic variables, and considerations for future directions.

Results: Complete resection remains the most effective and only potentially curative therapy for hilar cholangiocarcinoma. Negative resection margins are associated with improved outcomes, and major hepatic resections have enhanced the likelihood of R0 resection. Portal vein embolization may be indicated in selected patients before extensive hepatic resection. Staging laparoscopy should be considered to detect occult metastatic disease. Orthotopic liver transplantation might be applicable for a highly selected subgroup.

Conclusions: Surgical resection including major hepatic resection remains the mainstay of treatment of hilar cholangiocarcinoma. Additional evidence is needed to fully define the role of orthotopic liver transplantation. Improvements in adjuvant therapy are essential for improving long-term outcome.
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http://dx.doi.org/10.1097/SLA.0b013e3181afe0abDOI Listing
August 2009

Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence.

Ann Surg 2008 Aug;248(2):273-9

Department of Surgery, Section of Surgical Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.

Background: Hilar cholangiocarcinoma is an uncommon tumor with a poor prognosis. We sought to evaluate recurrence patterns and prognostic factors for disease-specific and disease-free survival in patients with surgically resected hilar cholangiocarcinoma in a single institution over the last 21 years.

Methods: From 1985 to 2006, all patients with hilar cholangiocarcinoma referred to a tertiary surgical clinic were evaluated. Demographic data, tumor characteristics, and outcome were analyzed retrospectively. Outcome was compared in patients treated in a recent era (1995-2006) compared with an earlier era (1985-1994).

Results: Of 91 patients evaluated, 22 patients (24%) had unresectable disease at presentation. Of the 69 patients submitted to laparotomy, resection was possible in 55% and the curative (R0) resection rate was 63%. In patients submitted to exploration, the operative (60 day) morbidity and mortality rates were 26% and 3%. Median disease-specific (DSS) and disease-free survival (DFS) were 29 and 20 months, respectively (median FU, 29 months.). In patients undergoing R0 resection, the median survival was prolonged (65 months). In the more recent era, resectability rates improved (69% vs. 17%; P = 0.0002), and this was associated with an improvement in median survival (30 vs. 4 months; P < 0.001). Factors predictive of improved disease-specific and disease-free survival included negative histologic margins, concomitant hepatic lobectomy, lack of nodal disease, well-differentiated histology, and an earlier tumor stage (P < 0.05). Concomitant liver resection was associated with a higher R0 resection rate (P = 0.006) and improved DSS and DFS (P = 0.005). In addition, concomitant liver resection was associated with a decreased incidence of initial recurrence in liver (P = 0.031).

Conclusions: In patients with hilar cholangiocarcinoma, concomitant hepatic resection is associated with improved DFS, DSS, and decreased hepatic recurrence. Therefore, hepatectomy combined with bile duct resection should be considered standard treatment.
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http://dx.doi.org/10.1097/SLA.0b013e31817f2bfdDOI Listing
August 2008

Transabdominal preperitoneal robotic inguinal hernia repair.

J Laparoendosc Adv Surg Tech A 2008 Jun;18(3):397-9

Department of Surgery, Division of General Surgery, University of Wisconsin School of Medicine and Public Health, Clinical Science Center, Madison, Wisconsin 53792, USA.

Inguinal hernias are commonly encountered at the time of radical retropubic prostatectomy. Concurrent inguinal hernia repair and prostatectomy is well described for the open and traditional laparoscopic approach. Robotic prostatectomy is the fastest growing treatment of prostate cancer. Concurrent robotic prostatectomy and robotic inguinal hernia repair has not been previously described. We recently performed such a procedure and describe our technique and impressions of this approach in this paper. The robotic surgical system allowed for the secure and efficient closure of the large transabdominal peritoneal flap following the preperitoneal placement of the mesh prosthesis. The robotic operating console provides the surgeon with a more comfortable, ergonomic position than is possible in a traditional laparoscopic approach. Robotic inguinal hernia repair is feasible immediately following robotic prostatectomy and may have certain advantages over alternative techniques.
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http://dx.doi.org/10.1089/lap.2007.0093DOI Listing
June 2008

The utility of intraoperative bilateral internal jugular venous sampling with rapid parathyroid hormone testing.

Ann Surg 2007 Jun;245(6):959-63

Section of Endocrine Surgery, Department of Surgery, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, USA.

Objective: To determine the utility of routine perioperative bilateral internal jugular venous sampling of parathyroid hormone (BIJ PTH) for localization during parathyroid surgery.

Summary Background Data: Venous sampling for PTH is a useful tool for parathyroid localization in patients undergoing reoperative surgery for hyperparathyroidism (HPT). With the development of intraoperative rapid PTH (ioPTH) testing, internal jugular PTH sampling with ioPTH testing to guide operative localization has been shown to be possible in select, difficult cases. However, the value of BIJ PTH for patients with HPT is unclear.

Methods: Between May 2004 and February 2006, 216 consecutive patients underwent neck exploration for HPT by one surgeon. Of these, 168 patients had BIJ PTH. Internal jugular venous blood was drawn from both left and right sides and analyzed for PTH using a rapid PTH assay. BIJ PTH levels were defined as lateralizing if >5% differences were observed between the right and left internal jugular vein samples.

Results: Of the 168 patients, 120 (71.4%) had a single parathyroid adenoma, 15 (8.9%) had double adenoma, and 33 (19.6%) had hyperplasia. The cure rate after parathyroidectomy was 98.2%. There were no complications related to BIJ PTH sampling. Sensitivity and positive predictive value of BIJ PTH for primary hyperparathyroidism were 80% and 71%, respectively. BIJ PTH was diagnostic in 95 cases (62.9%) in primary HPT. BIJ PTH successfully localized an abnormal gland in 26 of 45 (57.8%) in patients with negative sestamibi scanning. BIJ PTH was especially helpful in 18 of 168 (10.7%) cases when intraoperative peripheral parathyroid hormone did not fall by 50% and BIJ PTH successfully localized the hyperfunctioning glands.

Conclusions: In patients with HPT, BIJ PTH is safe and effective, providing additional localization information in the majority of cases. BIJ PTH is particularly useful in the setting of negative sestamibi scanning and in complex multigland disease cases.
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http://dx.doi.org/10.1097/01.sla.0000255578.11198.ffDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876969PMC
June 2007

Robotic foregut surgery.

Int J Med Robot 2006 Dec;2(4):287-92

University of Wisconsin School of Medicine and Public Health, Department of Surgery, Madison, WI, USA.

Background: Computer-assisted surgical systems, or surgical robots as they are more commonly called, are complex new devices which may be used to perform minimally invasive surgical procedures. There are certain technical limitations to a traditional laparoscopic approach that these devices can help a surgeon to overcome. Several surgical teams have applied these new devices to surgical procedures of the upper gastrointestinal tract and foregut.

Methods: A retrospective review of the currently published literature on robotic foregut surgery.

Results: Robotic foregut surgery appears to be feasible and safe. These procedures may be associated with increased operative time and cost when compared to their traditional laparoscopic counterparts. Procedures that require complex manoeuvres, delicate dissection, or a magnified high-definition image may be best suited to a computer-assisted approach.

Conclusions: Robotic foregut surgery is an exciting new field with tremendous potential for growth and dissemination.
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http://dx.doi.org/10.1002/rcs.108DOI Listing
December 2006

[A case of an epithelial cyst arising in the intrapancreatic accessory spleen].

Nihon Shokakibyo Gakkai Zasshi 2006 Dec;103(12):1391-6

Department of Surgery, Ise Municipal Hospital.

A 59-year old woman was admitted to our hospital for further examination of a cystic lesion detected in the tail of the pancreas. Imaging studies showed a 35-mm-diameter cystic lesion with septa and mural nodule at the same site. The mural nodule of the cyst was thick and was enhanced. Partial resection of the tail pancreas was performed with a preoperative diagnosis of pancreatic cystic tumor. The resected specimen showed mulitlobular cyst. Histologically, the internal surface of the cyst was covered with stratified squamous cells and the mural nodule of the cyst was spleen tissue. The final diagnosis was an epithelial cyst derived from an accessory spleen in the pancreas.
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December 2006

Anti-CD137 monoclonal antibody administration augments the antitumor efficacy of dendritic cell-based vaccines.

Cancer Res 2004 Nov;64(22):8411-9

Division of Surgical Oncology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.

In weakly and poorly immunogenic tumor models, we examined the effects of stimulating CD137 (4-1BB) in vivo by administering anti-CD137 monoclonal antibody after tumor lysate-pulsed dendritic cell (TP-DC) vaccination. TP-DC subcutaneous vaccination induced a transient up-regulation of CD137 on T cells and natural killer (NK) cells within vaccine-primed lymph nodes (VPLNs). In established pulmonary and subcutaneous tumor models, anti-CD137 synergistically enhanced tumor regression after TP-DC vaccination. In the subcutaneous tumor model, the combined therapy resulted in improved survival. Combined therapy also resulted in improved local control of subcutaneous tumor after surgical resection. Anti-CD137 polarized the cytokine release of VPLNs and spleen cells in response to tumor antigen toward a type 1 (interferon-gamma) versus a type 2 (interleukin-4) profile. Cell depletion and the use of knockout animals identified that CD8(+), CD4(+), and NK cells were involved in the tumor rejection response and that CD8(+) cells had the major effector role. Anti-CD137 administration resulted in increased proliferation of adoptively transferred OT-1 CD8(+) T cells in the VPLNs of mice inoculated with B16-OVA TP-DCs. Polarization toward type 1 (interferon-gamma) versus type 2 (interleukin-4) was also observed with the OT-1 cells from VPLNs and spleen cells after anti-CD137 injections. This polarization effect was abrogated by the in vivo depletion of NK cells. These findings indicate that the adjuvant effect of anti-CD137 given in conjunction with TP-DC vaccination is associated with the polarization of T effector cells toward a type 1 response to tumor antigen and is mediated via NK cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-04-0590DOI Listing
November 2004

Radiotherapy potentiates the therapeutic efficacy of intratumoral dendritic cell administration.

Cancer Res 2003 Dec;63(23):8466-75

Departments of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA.

We examined whether radiotherapy (RT) could enhance the efficacy of dendritic cell (DC)-based immunotherapy of cancer. Mice bearing s.c. D5 melanoma or MCA 205 sarcoma tumors were treated with intratumoral (i.t.) injections of bone marrow-derived unpulsed DCs in combination with local fractionated tumor irradiation. DC administration alone slightly inhibited D5 tumor growth and had no effect on MCA 205. RT alone caused a modest inhibition of both tumors. DC administration combined with RT inhibited D5 and MCA 205 tumor growth in an additive and synergistic manner, respectively. In both tumor models, RT intensified the antitumor efficacy of DC administration independent of apoptosis or necrosis within the tumor mass. Combination treatment of i.t. DCs plus RT was superior to s.c. injections of tumor lysate-pulsed DCs plus interleukin 2 in inhibiting D5 tumor growth and prolonging survival of mice. Splenocytes from mice treated with i.t. DCs plus RT contained significantly more tumor-specific, IFN-gamma-secreting T cells compared with control groups. Moreover, adoptive transfer of these splenocytes mediated significant tumor regression in mice bearing established pulmonary metastases. Combined treatment followed by resection of residual s.c. tumor conferred protective immunity against a subsequent i.v. tumor challenge. Furthermore, i.t. DC plus RT treatment of s.c. tumor in mice bearing concomitant pulmonary metastases resulted in a significant reduction of lung tumors. i.t. DC administration combined with RT induces a potent local and systemic antitumor response in tumor-bearing mice. This novel regimen may be beneficial in the treatment of human cancers.
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December 2003

Antitumor reactivity of anti-CD3/anti-CD28 bead-activated lymphoid cells: implications for cell therapy in a murine model.

J Immunother 2003 May-Jun;26(3):222-33

The Division of Surgical Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, USA.

Ligation of TCR and CD28 expressed on T cells via mAbs results in activation of T cells capable of tumor destruction in adoptive immunotherapy. In a murine model, the authors examined in vitro activation conditions utilizing plate-immobilized and bead-conjugated mAbs that bind to CD3 and CD28. Bead-activated tumor-draining lymph node (TDLN) cells demonstrated superior cytokine (IFN-gamma, GM-CSF, IL-2, and IL-10) secretion and mediated tumor regression more efficiently compared with plate-activated cells. The bead-activated TDLN cells had a significantly higher percentage of CD4+ cells compared with plate-activated cells. On a per-cell basis, positively selected CD4+ cells activated with bead-coupled or plate immobilized mAbs mediated tumor-specific regression equally. Bead-activated CD4+ TDLN cells demonstrated significantly higher levels of tumor specific IL-2 secretion compared with plate-activated CD4+ cells that may provide helper function to CD8+ effector cells. The antitumor reactivity of bead-activated lymphoid cells depended upon their source. TDLN cells after bead activation were more potent than splenocytes from tumor-bearing hosts in mediating tumor regression in vivo. Bead-activated LN cells and splenocytes from nontumor-bearing hosts demonstrated nonspecific cytokine secretion and minimal efficacy in adoptive immunotherapy. At minimal doses of IL-2, the antitumor reactivity of bead-activated TDLN cells was significantly enhanced. Anti-CD3/anti-CD28 bead activation of tumor-primed T cells represents an efficient method to generate effector cells for immunotherapy.
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http://dx.doi.org/10.1097/00002371-200305000-00006DOI Listing
January 2004

Polarization effects of 4-1BB during CD28 costimulation in generating tumor-reactive T cells for cancer immunotherapy.

Cancer Res 2003 May;63(10):2546-52

Division of Surgical Oncology, University of Michigan, Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0932, USA.

Using murine tumor-draining lymph node (TDLN) cells, we investigated the polarization effect of 4-1BB (CD137) during CD28 costimulation in generating antitumor T cells. Costimulation of TDLN cells through the newly induced 4-1BB molecules, CD3, and CD28 using monoclonal antibodies significantly enhanced cell proliferation. The greater cell yield with 4-1BB signaling appeared to be related to the inhibition of activation-induced cell death. Activation of TDLN cells through 4-1BB in addition to CD3/CD28 signaling shifted T-cell responses toward a type 1 cytokine pattern because 4-1BB ligation plus CD3/CD28 stimulation significantly augmented type 1 cytokine (e.g., IFN-gamma) and granulocyte macrophage colony-stimulating factor secretion. By contrast, type 2 cytokine (e.g., interleukin 10) secretion by the activated TDLN cells was significantly reduced. The in vivo antitumor reactivity of TDLN cells activated through 4-1BB in conjunction with CD3/CD28 pathways was examined using an adoptive immunotherapy model. The number of pulmonary metastases was significantly reduced and survival was prolonged after the transfer of anti-CD3/anti-CD28/anti-4-1BB-activated TDLN cells compared with an equivalent number of cells activated without anti-4-1BB. The antitumor effect through 4-1BB involvement during CD28 costimulation was dependent on IFN-gamma production and abrogated after IFN-gamma neutralization. By contrast, interleukin 10 neutralization resulted in significantly enhanced tumor regression. These results indicate that costimulation of TDLN cells through newly induced 4-1BB and CD3/CD28 signaling can significantly increase antitumor reactivity by shifting T-cell responses toward a type 1 cytokine pattern while concomitantly decreasing type 2 responses.
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May 2003