Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ+CD4-CD8-NK1.1- innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαβTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαβTs comprised ∼75% of the total intratumoral IL17+ cells. Moreover, iαβT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαβT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4+ and CD8+ T-cell expansion/activation and tumor protection. Collectively, iαβTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. SIGNIFICANCE: We found that iαβTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαβTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy.
|Number of pages||18|
|State||Published - 2019|
Bibliographical noteFunding Information:
This work was supported by NIH grants CA168611 (G. Miller), CA203105 (G. Miller), CA215471 (G. Miller), CA19311 (G. Miller), and DK106025 (G. Miller), the Knight Cancer Institute NCI P30 CA069533 (L.M. Coussens and R.C. Sears), the Brenden-Colson Center for Pancreatic Care (L.M. Coussens, S.M. Liudahl, K.R. Leis, J. Link, R.C. Sears, S. Sivagnanam, J. Goecks), Stand Up To Cancer– Lustgarten Foundation, Pancreatic Cancer Convergence Dream Team Translational Research Grant (SU2-AACR-DT14-14; L.M. Coussens and S.M. Liudahl), Stand Up To Cancer (SU2C) is a Division of the Entertainment Industry Foundation administered by the American Association for Cancer Research, the Scientific Partner of SU2C; and a resident research fellowship from the American Society for Colorectal Surgery (M. Hundeyin).
D. Saxena has ownership interest (including stock, patents, etc.) in Periomicscare LLC. L.M. Coussens reports receiving commercial research grants from Acerta Pharma, LLC, Deciphera Pharmaceuticals, Roche Glycart AG, and Syndax Pharmaceuticals, Inc.; reports receiving other commercial research support from Plexxikon Inc, Pharmacyclics, Inc., Acerta Pharma, LLC, Deciphera Pharmaceuticals, Genentech, Inc., Roche Glycart AG, Cell Signaling Technologies, and NanoString Technologies, Inc.; is a member of the Pharmacy-clics, Inc. steering committee for PCYC-1137-CA (NCT02436668); and is a consultant/advisory board member for Syndax Pharmaceuticals, Inc., Cancer Research Institute (CRI), The V Foundation for Cancer Research, Cancer Research United Kingdom (CRUK) Early Detection (EDx) Research Committee, Starr Cancer Consortium, NIH/NCI-Frederick National Laboratory Advisory Committee (FNLAC), Cell Signaling Technologies, Carisma Therapeutics Inc., Verseau Therapeutics, Inc., Zymeworks, Inc., (P30) Melvin and Bren Simon Cancer Center, Indiana University, (P30) Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology, (P30) Salk Institute Cancer Center, Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Dana-Farber Cancer Center Breast SPORE. No potential conflicts of interest were disclosed by the other authors.
© 2019 American Association for Cancer Research.
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