Duhen et al. show that various human primary and metastatic tumors (but not peripheral blood) contain CD8+ T cells that express both CD103 and CD39 as a result of prolonged TCR stimulation in the presence of TGFβ. These TILs exhibit an exhausted, tissue-resident memory phenotype, possess a highly clonal TCR repertoire, and express relatively low levels of IFNγ and TNFα, however they proliferate within the tumor and produce granzyme B. Following in vitro expansion, CD103+CD39+CD8+ TILs were tumor-reactive and cytotoxic, and their frequency correlated with increased survival in patients with head and neck squamous cell carcinoma.
Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103(+)CD39(+) tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103(+)CD39(+) CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. CD103(+)CD39(+) CD8 TILs also efficiently kill autologous tumor cells in a MHC-class I-dependent manner. Finally, higher frequencies of CD103(+)CD39(+) CD8 TILs in patients with head and neck cancer are associated with better overall survival. Our data thus describe an approach for detecting tumor-reactive CD8 TILs that will help define mechanisms of existing immunotherapy treatments, and may lead to future adoptive T-cell cancer therapies.
Author Info: (1) AgonOx, Inc., 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. thomas.duhen@agonox.com. (2) Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan
Author Info: (1) AgonOx, Inc., 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. thomas.duhen@agonox.com. (2) Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. (3) AgonOx, Inc., 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. (4) AgonOx, Inc., 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. (5) Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. (6) Department of Pathology, Leiden University Medical Center, P1-43, LUMC, Albinusdreef 2, 2333, Leiden, The Netherlands. (7) Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. (8) AgonOx, Inc., 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. (9) Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. (10) Pacific Northwest National Laboratory, Computational Biology and Bioinformatics Group, MSIN: J4-33, 902 Battelle Boulevard, PO Box 999, Richland, WA, 99352, USA. (11) Medical Data Research Center, Providence Saint Joseph's Health, 9205 SW Barnes Road, Portland, OR, 97225, USA. (12) Medical Data Research Center, Providence Saint Joseph's Health, 9205 SW Barnes Road, Portland, OR, 97225, USA. (13) Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. (14) Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. (15) AgonOx, Inc., 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. andrew.weinberg@providence.org. Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan Street 2N35, Portland, OR, 97213, USA. andrew.weinberg@providence.org.
