The existence of naturally-occurring, tumor-reactive T-cells in human cancer has rationalized the application of immunotherapy in oncology, however the immunobiology of spontaneous tumor-reactive T-cells in cancer is not well-defined due to difficulties in identifying and validating these responses. The ability to identify and characterize rare tumor-reactive T cells has strong prognostic value and holds the potential to enable various forms of immunotherapy, including adoptive T cell therapy, TCR gene therapy and immune checkpoint inhibition. In our attempt to explore the immunobiology of naturally-occurring immune responses in patients, we have now elucidated CD137 as a biomarker for bona fide naturally-occurring, tumor-reactive T-cells in cancer and developed a rapid, accurate system to comprehensively isolate tumor infiltrating lymphocytes (TILs) with tumor-rejecting capability directly from resected tumors. CD137+ TILs from various tumor types recognized autologous and HLA-matched tumor in an HLA-restricted manner, resulting in proflammatory cytokine production and cancer killing in vitro, and tumor growth inhibition in vivo; CD137-negative TILs did not. More so, multiparameter phenotyping of the CD137+ TIL subset revealed a vast network of expressed negative immunoregulatory molecules and opportunities for immune checkpoint inhibition. Our findings implicate a role for CD137 in the immunobiology of human cancer where it is preferentially expressed on the tumor-reactive TIL subset, and provides a new roadmap for the rational design of cancer immunotherapy trials.
Citation Format: Daniel J. Powell, Jr. Identification and enrichment for rare naturally occurring tumor-reactive T cells in the tumor microenvironment reveals new and diverse opportunities for cancer immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A85.
- ©2015 American Association for Cancer Research.