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Cancer Immunology Research

Timothy Chao, Emma E Furth, Robert H Vonderheide
Tumor-associated neutrophils are increasingly recognized for their ability to promote tumor progression, mediate resistance to therapy, and regulate immunosuppression. Evidence from various murine models has shown that the chemokine receptor CXCR2 attracts neutrophil into tumors and, therefore, represents a tractable therapeutic target. Here, we report prominent expression of a neutrophil gene signature in a subset of human pancreatic adenocarcinoma (PDA). CXCL5 was the most prominently expressed CXCR2 ligand in human PDA, and its expression was higher in PDA than in any other common tumor represented in The Cancer Genome Atlas...
October 13, 2016: Cancer Immunology Research
Margaretha G M Roemer, Ranjana H Advani, Robert A Redd, Geraldine S Pinkus, Yasodha Natkunam, Azra H Ligon, Courtney F Connelly, Christine J Pak, Christopher D Carey, Sarah E Daadi, Bjoern Chapuy, Daphne de Jong, Richard T Hoppe, Donna S Neuberg, Margaret A Shipp, Scott J Rodig
In classical Hodgkin Lymphoma (cHL), malignant Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple mechanisms, including perturbed antigen presentation and enhanced PD-1 signaling. HRS cell expression of the PD-1 ligands is attributable, in part, to copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) Amplification of PD-L1/PD-L2 is associated with advanced clinical stage and inferior progression-free survival (PFS) following frontline (induction) therapy. The relationships between altered expression of β2-microglobulin (β2M), MHC class I, and MHC class II by HRS cells, PD-L1/PD-L2 amplification, and clinical outcome in cHL are poorly defined...
October 13, 2016: Cancer Immunology Research
Ruoxu Dou, Reiko Nishihara, Yin Cao, Tsuyoshi Hamada, Kosuke Mima, Atsuhiro Masuda, Yohei Masugi, Yan Shi, Mancang Gu, Wanwan Li, Annacarolina da Silva, Katsuhiko Nosho, Xuehong Zhang, Jeffrey A Meyerhardt, Edward L Giovannucci, Andrew T Chan, Charles S Fuchs, Zhi Rong Qian, Shuji Ogino
Experimental evidence suggests that the let-7 family of noncoding RNAs suppresses adaptive immune responses, contributing to immune evasion by the tumor. We hypothesized that the amount of let-7a and let-7b expression in colorectal carcinoma might be associated with limited T-lymphocyte infiltrates in the tumor microenvironment and worse clinical outcome. Utilizing the molecular pathological epidemiology resources of 795 rectal and colon cancers in two U.S.-nationwide prospective cohort studies, we measured tumor-associated let-7a and let-7b expression levels by quantitative reverse-transcription PCR, and CD3(+), CD8(+), CD45RO (PTPRC)(+), and FOXP3(+) cell densities by tumor tissue microarray immunohistochemistry and computer-assisted image analysis...
October 13, 2016: Cancer Immunology Research
Geok Choo Sim, Chengwen Liu, Ena Wang, Hui Liu, Caitlin Creasy, Zhimin Dai, Willem W Overwijk, Jason Roszik, Francesco M Marincola, Patrick Hwu, Elizabeth A Grimm, Laszlo G Radvanyi
Clinical responses to high-dose IL-2 therapy are limited due to selective expansion of CD4+CD25+oxp3+ T-regulatory cells (Tregs) especially ICOS+Tregs, rather than NK cells and effector T cells. These ICOS+Tregs are highly suppressive and constitutively express high levels of IL-2Ralpha (CD25) and CD39. Here, we characterized the effect of a mutant form of IL-2 (F42K), which preferentially binds to the lower affinity IL-2Rbetagamma with reduced binding to CD25, on Tregs, effector NK cells, and T-cell subsets...
October 3, 2016: Cancer Immunology Research
Xiao X Wei, Stephen Chan, Serena Kwek, Jera Lewis, Vinh Dao, Li Zhang, Matthew R Cooperberg, Charles J Ryan, Amy M Lin, Terence W Friedlander, Brian Rini, Christopher Kane, Jeffry P Simko, Peter R Carroll, Eric J Small, Lawrence Fong
Granulocytic-macrophage colony-stimulating factor (GM-CSF) is used as an adjuvant in cancer vaccine trials and has the potential to enhance antitumor efficacy with immunotherapy; however, its immunologic effects are not fully understood. Here, we report results from a phase I study of neoadjuvant GM-CSF in patients with localized prostate cancer undergoing radical prostatectomy. Patients received subcutaneous injections of GM-CSF (250 μg/m(2)/day) daily for 2 weeks (cohort 1; n = 6), 3 weeks (cohort 2; n = 6), or 4 weeks (cohort 3; n = 6)...
September 29, 2016: Cancer Immunology Research
Elliott J Brea, Claire Y Oh, Eusebio Manchado, Sadna Budhu, Ron S Gejman, George Mo, Patrizia Mondello, James E Han, Casey A Jarvis, David Ulmert, Qing Xiang, Aaron Y Chang, Ralph J Garippa, Taha Merghoub, Jedd D Wolchok, Neal Rosen, Scott W Lowe, David A Scheinberg
The major histocompatibility complex I (MHC-I) presents antigenic peptides to tumor-specific CD8+ T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped...
September 28, 2016: Cancer Immunology Research
Douglas B Johnson, Garrett M Frampton, Matthew J Rioth, Erik Yusko, Yaomin Xu, Xingyi Guo, Riley C Ennis, David Fabrizio, Zachary R Chalmers, Joel Greenbowe, Siraj M Ali, Sohail Balasubramanian, James X Sun, Yuting He, Dennie T Frederick, Igor Puzanov, Justin M Balko, Justin M Cates, Jeffrey S Ross, Catherine Sanders, Harlan Robins, Yu Shyr, Vincent Miller, Philip J Stephens, Ryan J Sullivan, Jeffrey A Sosman, Christine M Lovly
Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next generation sequencing (NGS) panel available in the clinic were correlated with response to anti-PD-1 in melanoma. Using archival melanoma samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers...
September 26, 2016: Cancer Immunology Research
Hweixian Leong Penny, Tyler R Prestwood, Nupur Bhattacharya, Fionna Sun, Justin A Kenkel, Matthew G Davidson, Lei Shen, Luis A Zuniga, E Scott Seeley, Reetesh Pai, Okmi Choi, Lorna Tolentino, Jinshan Wang, Joseph L Napoli, Edgar G Engleman
Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Because retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APC(Min/+) mice, a model that recapitulates FAP in most respects...
September 16, 2016: Cancer Immunology Research
Shalin Shah, James E Ward, Riyue Bao, Curtis R Hall, Bruce E Brockstein, Jason J Luke
Anti-Programed Death 1 (PD-1) is standard immunotherapy for multiple cancers and the expression of one of its ligands, PD-L1, has been described in germ cell tumors (GCTs). Neither the clinical activity of anti-PD-1 nor the incidence of an immunoresponsive tumor microenvironment has been described for GCTs. A patient initially diagnosed with melanoma via fine needle aspiration was treated with one dose of antibody to PD-1. A core needle biopsy was subsequently performed to acquire sufficient tissue for molecular analysis, which led to a change in diagnosis to metastatic embryonal carcinoma...
September 16, 2016: Cancer Immunology Research
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October 2016: Cancer Immunology Research
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October 2016: Cancer Immunology Research
Elizabeth Scheid, Pierre Major, Alain Bergeron, Olivera J Finn, Russell D Salter, Robin Eady, Bader Yassine-Diab, David Favre, Yoav Peretz, Claire Landry, Sebastien Hotte, Som D Mukherjee, Gregory A Dekaban, Corby Fink, Paula J Foster, Jeffery Gaudet, Jean Gariepy, Rafick-Pierre Sekaly, Louis Lacombe, Yves Fradet, Ronan Foley
MUC1 is a glycoprotein expressed on the apical surface of ductal epithelial cells. Malignant transformation results in loss of polarization and overexpression of hypoglycosylated MUC1 carrying truncated carbohydrates known as T or Tn tumor antigens. Tumor MUC1 bearing Tn carbohydrates (Tn-MUC1) represent a potential target for immunotherapy. We evaluated the Tn-MUC1 glycopeptide in a human phase I/II clinical trial for safety that followed a preclinical study of different glycosylation forms of MUC1 in rhesus macaques, whose MUC1 is highly homologous to human MUC1...
October 2016: Cancer Immunology Research
Blanca Homet Moreno, Jesse M Zaretsky, Angel Garcia-Diaz, Jennifer Tsoi, Giulia Parisi, Lidia Robert, Katrina Meeth, Abibatou Ndoye, Marcus Bosenberg, Ashani T Weeraratna, Thomas G Graeber, Begoña Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas
The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor-host interactions, we evaluated three syngeneic murine tumor models, the BRAF(V600E)-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAF(V600E) mutation and PTEN loss (BRAF(V600E)/PTEN(-/-))...
October 2016: Cancer Immunology Research
David B Page, Jianda Yuan, David Redmond, Y Hanna Wen, Jeremy C Durack, Ryan Emerson, Stephen Solomon, Zhiwan Dong, Phillip Wong, Christopher Comstock, Adi Diab, Janice Sung, Majid Maybody, Elizabeth Morris, Edi Brogi, Monica Morrow, Virgilio Sacchini, Olivier Elemento, Harlan Robins, Sujata Patil, James P Allison, Jedd D Wolchok, Clifford Hudis, Larry Norton, Heather L McArthur
In early-stage breast cancer, the degree of tumor-infiltrating lymphocytes (TIL) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryoimmunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab...
October 2016: Cancer Immunology Research
Adrienne H Long, Steven L Highfill, Yongzhi Cui, Jillian P Smith, Alec J Walker, Sneha Ramakrishna, Rana El-Etriby, Susana Galli, Maria G Tsokos, Rimas J Orentas, Crystal L Mackall
Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CAR) have shown impressive activity against B-cell malignancies, and preliminary results suggest that T cells expressing a first-generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18 of 18 (100%) of osteosarcomas, 2 of 15 (13%) of rhabdomyosarcomas, and 7 of 35 (20%) of Ewing sarcomas expressed GD2...
October 2016: Cancer Immunology Research
Xinqi Wu, Anita Giobbie-Hurder, Xiaoyun Liao, Donald Lawrence, David McDermott, Jun Zhou, Scott Rodig, F Stephen Hodi
Immune recognition of tumor targets by specific cytotoxic lymphocytes is essential for the effective rejection of tumors. A phase I clinical trial of ipilimumab (an antibody that blocks CTLA-4 function) in combination with bevacizumab (an antibody that inhibits angiogenesis) in patients with metastatic melanoma found favorable clinical outcomes were associated with increased tumor endothelial activation and lymphocyte infiltration. To better understand the underlying mechanisms, we sought features and factors that changed as a function of treatment in patients...
October 2016: Cancer Immunology Research
Barbora Brodská, Petra Otevřelová, Kateřina Kuželová
The expression on the surface of tumor cells of ligands for the PD-1 inhibitory receptor prevents the antitumor immune response and is considered to be a negative prognostic factor in a variety of solid tumors as well as in hematologic malignancies. To determine if it were possible to analyze PD-L1 with PCR-based methods, we assessed the expression of PD-L1 in primary samples from patients with acute myeloid leukemia, in healthy donors, and in a panel of cell lines, by means of flow cytometry, RT-PCR, and Western blotting...
October 2016: Cancer Immunology Research
Guillermo de Velasco, Diana Miao, Martin H Voss, A Ari Hakimi, James J Hsieh, Nizar M Tannir, Pheroze Tamboli, Leonard J Appleman, W Kimryn Rathmell, Eliezer M Van Allen, Toni K Choueiri
Patients with metastatic renal cell carcinoma (mRCC) have better overall survival when treated with nivolumab, a cancer immunotherapy that targets the immune checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients treated with nivolumab seemed to experience the greatest overall survival benefit, compared with patients with favorable or intermediate risk, in an analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups...
October 2016: Cancer Immunology Research
Wenjie Yin, Dorothée Duluc, HyeMee Joo, Yaming Xue, Chao Gu, Zhiqing Wang, Lei Wang, Richard Ouedraogo, Lance Oxford, Amelia Clark, Falguni Parikh, Seunghee Kim-Schulze, LuAnn Thompson-Snipes, Sang-Yull Lee, Clay Beauregard, Jung-Hee Woo, Sandra Zurawski, Andrew G Sikora, Gerard Zurawski, SangKon Oh
Human papillomavirus (HPV), particularly HPV16 and HPV18, can cause cancers in diverse anatomical sites, including the anogenital and oropharyngeal (throat) regions. Therefore, development of safe and clinically effective therapeutic vaccines is an important goal. Herein, we show that a recombinant fusion protein of a humanized antibody to CD40 fused to HPV16.E6/7 (αCD40-HPV16.E6/7) can evoke HPV16.E6/7-specific CD8(+) and CD4(+) T-cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40Tg) mice in vivo The combination of αCD40-HPV16...
October 2016: Cancer Immunology Research
George Plitas, Alexander Y Rudensky
The immune system of vertebrate animals has evolved to mount an effective defense against a diverse set of pathogens while minimizing transient or lasting impairment in tissue function that could result from the inflammation caused by immune responses to infectious agents. In addition, misguided immune responses to "self" and dietary antigens, as well as to commensal microorganisms, can lead to a variety of inflammatory disorders, including autoimmunity, metabolic syndrome, allergies, and cancer. Regulatory T cells expressing the X chromosome-linked transcription factor Foxp3 suppress inflammatory responses in diverse biological settings and serve as a vital mechanism of negative regulation of immune-mediated inflammation...
September 2, 2016: Cancer Immunology Research
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