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Cancer Immunology Research

Hagma H Workel, Joyce M Lubbers, Roland Arnold, Thalina M Prins, Pieter van der Vlies, Kim de Lange, Tjalling Bosse, Inge C Van Gool, Florine A Eggink, Maartje Ca Wouters, Fenne L Komdeur, Elisabeth C van der Slikke, Carien L Creutzberg, Arjan Kol, Annechien Plat, Mark Glaire, David N Church, Hans W Nijman, Marco de Bruyn
The chemokine CXCL13 mediates recruitment of B cells to tumors and is essential for the formation of tertiary lymphoid structures (TLSs). TLSs are thought to support antitumor immunity and are associated with improved prognosis. However, it remains unknown whether TLSs are formed in response to the general inflammatory character of the tumor microenvironment, or rather, are induced by (neo)antigen-specific adaptive immunity. We here report on the finding that the transforming growth factor beta (TGFβ)-dependent CD103+CD8+ tumor-infiltrating T-cell (TIL) subpopulation expressed and produced CXCL13...
March 14, 2019: Cancer Immunology Research
Ines P Nearchou, Kate Lillard, Christos G Gavriel, Hideki Ueno, David J Harrison, Peter D Caie
Both immune profiling and tumor budding significantly correlate with colorectal cancer patient outcome but are traditionally reported independently. This study evaluated the association and interaction between lymphocytic infiltration and tumor budding, coregistered on a single slide, in order to determine a more precise prognostic algorithm for patients with stage II colorectal cancer. Multiplexed immunofluorescence and automated image analysis were used for the quantification of CD3+ CD8+ T cells, and tumor buds (TBs), across whole slide images of three independent cohorts (training cohort: n = 114, validation cohort 1: n = 56, validation cohort 2: n = 62)...
March 7, 2019: Cancer Immunology Research
Dongqiang Zeng, Meiyi Li, Rui Zhou, Jingwen Zhang, Huiying Sun, Min Shi, Jianping Bin, Yulin Liao, Jinjun Rao, Wangjun Liao
Tumor microenvironment (TME) cells constitute a vital element of tumor tissue. Increasing evidence has elucidated their clinicopathological significance in predicting outcomes and therapeutic efficacy. Nonetheless, no studies have reported a systematic analysis of cellular interactions in the tumor microenvironment. In this study, we comprehensively estimated the TME infiltration patterns of 1,524 gastric cancer patients and systematically correlated the TME phenotypes with genomic characteristics and clinicopathological features of gastric cancer using two proposed computational algorithms...
March 6, 2019: Cancer Immunology Research
Sarah Ahn, Jingjing Li, Chuang Sun, Keliang Gao, Koichi Hirabayashi, Hongxia Li, Barbara Savoldo, Rihe Liu, Gianpietro Dotti
Tumors are inherently heterogeneous in antigen expression and escape from immune surveillance due to antigen loss remains one of the limitations of targeted immunotherapy. Despite the clinical use of adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells in lymphoblastic leukemia, treatment failure due to epitope loss occurs. Targeting multiple tumor-associated antigens (TAA) may thus improve the outcome of CAR-T cell therapies. CARs developed to simultaneously target multiple targets are limited by the large size of each single-chain variable fragment and compromised protein folding when several single chains are linearly assembled...
March 6, 2019: Cancer Immunology Research
Ji Hoon Oh, Myeong Joon Kim, Seong Jin Choi, Young Ho Ban, Heung Kyu Lee, Eui-Cheol Shin, Kyung-Mi Lee, Sang-Jun Ha
The importance of natural killer (NK) cells in the early immune response to viral or bacterial infection is well known. However, the phenotype, function, and physiological role of NK cells during the late stage of persistent viral infection have not been extensively studied. Here, we characterized NK cells in mice persistently infected with lymphocytic choriomeningitis virus clone 13 and showed that in contrast to NK cells from acutely infected or uninfected mice, NK cells from chronically infected mice expressed a terminally differentiated phenotype, stronger cytotoxicity, and reduced inhibitory receptor expression...
February 26, 2019: Cancer Immunology Research
Anne Hansen Ree, Vigdis Nygaard, Hege G Russnes, Daniel Heinrich, Vegard Nygaard, Christin Johansen, Inger R Bergheim, Eivind Hovig, Klaus Beiske, Anne Negård, Anne-Lise Borresen-Dale, Kjersti Flatmark, Gunhild M Maelandsmo
Most patients whose large bowel cancer has spread to other organs do not respond to immune therapy. We detected a rare gene mutation, termed 9p24.1 copy-number gain, in an otherwise incurable colorectal cancer that provoked an immune therapy response. We identified this gene mutation by gene-panel sequencing of DNA from a liver metastasis biopsy from a patient who had disease refractory to standard therapies. Following immune checkpoint blockade with pembrolizumab (anti-PD-1), the patient experienced conversion of the tumor phenotype from one with epithelial features to that of an inflamed microenvironment, detected by high-resolution RNA sequencing...
February 25, 2019: Cancer Immunology Research
Tommaso Cavalleri, Paolo Bianchi, Gianluca Basso, Giuseppe Celesti, Fabio Grizzi, Paola Bossi, Luana Greco, Calogero Pitrone, Emanuele Valtorta, Gianluca Mauri, Mauro Truini, Filippo Gustavo Dall'Olio, Giovanni Brandi, Andrea Sartore-Bianchi, Luigi Ricciardiello, Valter Torri, Lorenza Rimassa, Salvatore Siena, Alberto Mantovani, Alberto Malesci, Luigi Laghi
The densities of CD3+ and CD8+ tumor-infiltrating lymphocytes (TILs), combined with TNM (tumor-node-metastasis) staging, have prognostic value for nonmetastatic colorectal cancer (CRC) patients. We compared the prognostic value of CD3+ and FoxP3+ TILs at the invasive front, TNM classifiers, and microsatellite (MS) status in a trial set of patients with stage II-III CRC (n = 413), by recursive partitioning with a classification and regression tree (CART). Significant prognostic factors and interactions were re-assessed by logistic regression and Cox proportional-hazards modeling in the trial and a validation set (n = 215) of patients with stage II CRC...
February 25, 2019: Cancer Immunology Research
Eric Krawczyk, Sergey N Zolov, Kevin Huang, Challice L Bonifant
The development of engineered T cells to treat acute myeloid leukemia (AML) is challenging due to difficulty in target selection and the need for robust T-cell expansion and persistence. We designed a T cell stimulated to kill AML cells based on recognition of the AML-associated surface marker CLEC12A, via secretion of a CLEC12AxCD3 bispecific "engager" molecule (CLEC12A-ENG). CLEC12A-ENG T cells are specifically activated by CLEC12A, are not toxic to hematopoietic progenitor cells, and exhibit antigen-dependent AML killing...
February 19, 2019: Cancer Immunology Research
Akihito Harusato, Emilie Viennois, Lucie Etienne-Mesmin, Shingo Matsuyama, Hirohito Abo, Satoru Osuka, Nicholas W Lukacs, Yuji Naito, Yoshito Itoh, Jian-Dong Li, Didier Merlin, Andrew T Gewirtz, Timothy L Denning
Gut microbiota and their metabolites are instrumental in regulating homeostasis at intestinal and extra-intestinal sites. However, the complex effects of prenatal and early postnatal microbial exposure on adult health and disease outcomes remain incompletely understood. Here, we showed that mice raised under germ-free conditions until weaning and then transferred to specific-pathogen free conditions, harbored altered microbiota composition, augmented inflammatory cytokine and chemokine expression, and were hyper-susceptible to colitis-associated tumorigenesis later in adulthood...
February 19, 2019: Cancer Immunology Research
Cornelia Hutmacher, Nicolas Núñez, Anna Rita Liuzzi, Burkhard Becher, Dario Neri
Recombinant human interleukin-2 (IL2) is being considered as a combination partner for immune checkpoint inhibitors in cancer therapy, but the product only has a narrow therapeutic window. Therefore, we used F8-IL2, an antibody-IL2 fusion protein capable of selective localization to the tumor site, in combination with antibodies against murine CTLA-4, PD-1, and PD-L1. In immunocompetent mice bearing CT26 tumors, the combination of F8-IL2 with CTLA-4 blockade was efficacious, leading to increased progression-free survival and protective immunity against subsequent tumor re-challenges...
February 19, 2019: Cancer Immunology Research
Paula Kroon, Elselien Frijlink, Victoria Iglesias-Guimarais, Andriy Volkov, Marit M Van Buuren, Ton N Schumacher, Marcel Verheij, Jannie Borst, Inge Verbrugge
To increase cancer immunotherapy success, PD-1 blockade must be combined with rationally selected treatments. Here, we examined, in a poorly immunogenic mouse breast cancer model, the potential of antibody-based immunomodulation and conventional anticancer treatments to collaborate with anti-PD-1 treatment. One requirement to improve anti-PD-1-mediated tumor control was to promote tumor-specific cytotoxic T-cell (CTL) priming, which was achieved by stimulating the CD137 costimulatory receptor. A second requirement was to overrule PD-1-unrelated mechanisms of CTL suppression in the tumor micro-environment (TME)...
February 19, 2019: Cancer Immunology Research
Sha Zhao, Shengxiang Ren, Tao Jiang, Bo Zhu, Xuefei Li, Chao Zhao, Yijun Jia, Jinpeng Shi, Limin Zhang, Xiaozhen Liu, Meng Qiao, Xiaoxia Chen, Chunxia Su, Hui Yu, Caicun Zhou, Jun Zhang, D Ross Camidge, Fred R Hirsch
Lack of response to treatment in most lung cancer patients suggests the value of broadening the benefit of anti-PD-1/PD-L1 monotherapy. Judicious dosing of anti-angiogenic agents such as apatinib (VEGFR2-TKI) can modulate the tumor immunosuppressive microenvironment, which contributes to resistance to anti-PD-1/PD-L1 treatment. We therefore hypothesized that inhibiting angiogenesis could enhance therapeutic efficacy of PD-1/PD-L1 blockade. Here, using a syngeneic lung cancer mouse model, we demonstrated that low-dose apatinib alleviated hypoxia, increased infiltration of CD8+ T cells, reduced recruitment of tumor-associated macrophages (TAMs) in tumor and decreased TGF-β amounts both in tumor and serum...
February 12, 2019: Cancer Immunology Research
Ziju Xu-Monette, Min Xiao, Qingyan Au, Raghav Padmanabhan, Bing Xu, Nicholas Hoe, Sandra Rodriguez-Perales, Raul Torres-Ruiz, Ganiraju Manyam, Carlo Visco, Yi Miao, Xiaohong Tan, Hongwei Zhang, Alexandar Tzankov, Jing Wang, Karen Dybkaer, Wayne Tam, Hua You, Govind Bhagat, Eric D Hsi, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Miguel A Piris, J Han van Krieken, Jane N Winter, Jason R Westin, Lan V Pham, L Jeffrey Medeiros, George Z Rassidakis, Yong Li, Gordon J Freeman, Ken H Young
PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for twelve types of cancer and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants...
February 11, 2019: Cancer Immunology Research
Adam D Cohen, Nikoletta Lendvai, Sarah Nataraj, Naoko Imai, Achim A Jungbluth, Ioanna Tsakos, Adeeb Rahman, Anna Hc Mei, Herman Singh, Katarzyna Zarychta, Seunghee Kim-Schulze, Andrew J Park, Ralph R Venhaus, R Katherine Alpaugh, Sacha Gnjatic, Hearn Jay Cho
Autologous stem cell transplant (autoSCT), the standard consolidation therapy for multiple myeloma, improves disease-free survival but is not curative. This could be an ideal setting for immunologic therapy. However, the immune milieu is impaired after autoSCT. We hypothesized that autologous lymphocyte infusion would restore immune competence, allowing immunotherapies such as cancer vaccines to elicit tumor antigen-specific immunity in the setting of autoSCT. In this pilot study (NCT01380145), we investigated safety, immunologic, and clinical outcomes of autologous lymphocyte infusion combined with peri-autoSCT immunotherapy with recombinant MAGE-A3 (a multiple myeloma-associated antigen) and adjuvant...
February 11, 2019: Cancer Immunology Research
Il-Kyu Kim, Choong-Hyun Koh, Insu Jeon, Kwang-Soo Shin, Tae-Seung Kang, Eun-Ah Bae, Hyungseok Seo, Hyun-Ja Ko, Byung-Seok Kim, Yeonseok Chung, Chang-Yuil Kang
Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant has been shown to promote antitumor immunity in mice and humans; however, the underlying mechanism of GM-CSF-induced antitumor immunity remains incompletely understood. In this study, we demonstrate that GM-CSF potentiates the efficacy of cancer vaccines through interleukin (IL)-9-producing T helper (Th9) cells. GM-CSF selectively enhanced Th9 cell differentiation by regulating the COX2-PGE2 pathway while inhibiting the differentiation of induced regulatory T (iTreg) cells in vitro and in vivo...
February 6, 2019: Cancer Immunology Research
Lukas W Pfannenstiel, Marcela Diaz-Montero, Ye F Tian, Joseph Scharpf, Jennifer Ko, Brian Gastman
Immune-checkpoint blockade enhances antitumor responses against cancers. One cancer type that is sensitive to checkpoint blockade is squamous cell carcinoma of the head and neck (SCCHN), which we use here to study limitations of this treatment modality. We observed that CD8+ tumor infiltrating lymphocytes (TIL) in SCCHN and melanoma express excess immune checkpoints components PD-1 and Tim-3 and are also CD27-/CD28-, a phenotype we previously associated with immune dysfunction and suppression. In ex vivo experiments, patients' CD8+ TIL with this phenotype suppressed proliferation of autologous peripheral blood T cells...
February 6, 2019: Cancer Immunology Research
Winifred Lo, Maria R Parkhurst, Paul F Robbins, Eric Tran, Yong-Chen Lu, Li Jia, Jared J Gartner, Anna Pasetto, Drew C Deniger, Parisa Malekzadeh, Thomas Shelton, Todd D Prickett, Satyajit Ray, Scott Kivitz, Biman C Paria, Isaac R Kriley, David S Schrump, Steven A Rosenberg
Adoptive cell therapy (ACT) with T cells targeting neoantigens can mediate durable responses in patients with metastatic cancer. Cell therapies targeting common shared antigens for epithelial cancers are not yet broadly available. Here we report the identification and characterization in one patient of T cell receptors (TCRs) recognizing mutated p53 p.R175H, which is shared among a subset of patients with cancer. Tumor-infiltrating lymphocytes (TILs) were screened for recognition of mutated neoantigens in a patient with metastatic colorectal cancer...
February 1, 2019: Cancer Immunology Research
Michele Mondini, Pierre-Louis Loyher, Pauline Hamon, Marine Gerbé De Thoré, Marie Laviron, Kévin Berthelot, Céline Clémenson, Benoit L Salomon, Christophe Combadière, Eric Deutsch, Alexandre Boissonnas
Radiation therapy (RT) represents one of the main anti-cancer approaches for the treatment of solid tumors. Beyond the expected direct effects of RT on tumor cells, evidence supporting the importance of an immune response to radiotherapy is growing. The balance between RT-mediated immunogenic and tolerogenic activity is ill-defined and deserves more attention. Herein, a murine model of head and neck squamous cell carcinoma (HNSCC) was used to demonstrate that RT upregulated CCL2 chemokine production in tumor cells, leading to a CCR2-dependent accumulation of tumor necrosis factor alpha (TNFα)-producing monocytes and CCR2+ regulatory T cells (Tregs)...
January 29, 2019: Cancer Immunology Research
Sonia Domingos-Pereira, Karthik Sathiyanadan, Stefano La Rosa, Lenka Polák, Mathieu F Chevalier, Rim Hojeij, Paul Martel, Laurent Derré, Jacques-Antoine Haefliger, Patrice Jichlinski, Denise Nardelli-Haefliger
Preclinical data shows that intravesical instillation of Ty21a/Vivotif®, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus-Calmette-Guérin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). Here we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor-regression towards the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 106 to 108 colony-forming units...
January 29, 2019: Cancer Immunology Research
Tadanobu Nagaya, Jay Friedman, Yasuhiro Maruoka, Fusa Ogata, Shuhei Okuyama, Paul E Clavijo, Peter L Choyke, Clint Allen, Hisataka Kobayashi
Near-infrared photoimmunotherapy (NIR-PIT) induces immunogenic cell death, but has mostly failed to induce durable antitumor responses in syngenic tumor mouse models. We hypothesized that adaptive immune resistance could be limiting durable responses after treatmemt with NIR-PIT. We investigated the effects of combining NIR-PIT targeting cell surface CD44 and PD-1 blockade in multiple syngeneic tumor models. In two of three models, NIR-PIT monotherapy halted tumor growth, enhanced dendritic cell tumor infiltration, and induced de novo tumor antigen-specific T-cell responses absent at baseline...
January 25, 2019: Cancer Immunology Research
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