Abstract B050: Identification of PD-1T TILs and CXCL13 as determinants for response to anti-PD-1 treatment using human tumor explants

Reinvigoration of tumor-specific T-cells by cancer immunotherapies, in particular PD-1/PD-L1 blocking agents, has greatly improved clinical outcome in multiple cancer types. Nevertheless, durable clinical benefit is currently limited to a small number of patients. To achieve a better understanding of the immunologic determinants of response to anti-PD-1 therapy, we assessed transcriptional and functional profiles of tumor-infiltrating lymphocyte (TIL) subsets from non-small cell lung cancer specimens. Thereby, we identified a transcriptionally distinct CD8 TIL pool with enriched capacity for tumor recognition. This TIL pool, termed PD-1T TILs, is characterized by bright PD-1 expression and constitutive CXCL13 secretion, which can mediate immune cell recruitment to tertiary lymphoid structures. Notably, the presence of PD-1T TILs correlates with response and survival in a small cohort of lung cancer patients treated with PD-1 blockade. To assess the role of PD-1T TILs and CXCL13 for response to PD-1 blockade in other cancer types, we developed a platform using human tumor explants to visualize immunologic responses to anti-PD-1 on a patient-specific level. Analysis of the cellular and soluble tumor microenvironment composition as well as of treatment-induced changes in tumor-infiltrating immune cells revealed immunologic responses to anti-PD-1 in 5 different cancer types. Of note, responding tumors in different tumor types were characterized by a clear enrichment in both PD-1T TILs and CXCL13 production. Collectively, our data reveal a distinct state of PD-1 bright lymphocytes that are enriched for tumor-reactivity in human cancer, making them an attractive proxy for the antitumor potential of the intratumoral T-cell pool. Furthermore, we established technology using human tumor explants to measure the immunologic response to T-cell checkpoint inhibition on a personalized basis. Finally, with this approach we identified PD-1T TILs and CXCL13 as determinants for response to anti-PD-1 in multiple cancer types, opening potential new avenues for therapeutic intervention and improved patient selection. Citation Format: Daniela S. Thommen, Viktor H. Koelzer, Petra Herzig, Marjolein de Bruijn, Paula Voabil, Marlous van den Braber, Karlijn Hummelink, Kim Monkhorst, Kirsten D. Mertz, Alfred Zippelius, John B.A.G. Haanen, Ton N.M. Schumacher. Identification of PD-1T TILs and CXCL13 as determinants for response to anti-PD-1 treatment using human tumor explants [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B050.