Abstract A181: Origin of tumor-elicited cytotoxic innate-like T-cell responses

In most murine cancer models and human patients, cell-mediated cytotoxicity is critical for the destruction of tumor cells. Conventional CD8+ T-cells, which possess cytotoxic capacity, are thus the targets of most cancer immunotherapies. However, tumors that are poorly antigenic, immunosuppressive, or have low T-cell infiltration are often resistant to CD8+ T-cell-centric modalities. Thus, exploring the roles of other cytotoxic immune cell types will complement and synergistically enhance the potency of current treatments. Recently, our lab identified a population of tumor-infiltrating innate-like T-cells (ILTCs), which constitutively express high levels of cytotoxic molecules, are closely juxtaposed to tumor cells, and readily induce cytolysis of transformed target cells. Although armed with a polyclonal T-cell receptor (TCR) repertoire similar to conventional T-cells, ILTCs are phenotypically unconventional and innate-like by the concomitant expression of activating and inhibitory receptors typically found on natural killer (NK) cells but not on conventional T-cells. The specificity of ILTC TCR is unknown, and the extent to which TCR engagement maintains ILTCs and activates their effector functions in the context of tumor also remains ill-defined. While ILTCs and conventional T-cells share a thymic origin, genome-wide analyses revealed a distinct epigenetic landscape in ILTCs compared to conventional T-cells, suggesting that ILTCs constitute a disparate lineage and that alternative selection processes drive their fate choice during thymic development. Here, we showed that commitment to ILTC fate is instructed by distinct TCR specificity. Utilizing TCR retrogenic models and adoptive cell transfer approach, we identified the thymic and circulating ILTC-lineage-committed progenitor. These precursors are continuously generated by adult hematopoiesis and replenish the ILTC pool as the tumor develops. By acutely ablating TCRs, we demonstrated that tumor-resident ILTCs continuously require TCR for their maintenance. Together, our results delineate the ontogeny of ILTCs. Their unique TCR specificity, homing pattern, and innate-like features make ILTC a powerful candidate for bioengineering and adoptive cellular therapy. Citation Format: Chun Chou, Saida Dadi, Briana G. Nixon, Ming Li. Origin of tumor-elicited cytotoxic innate-like T-cell responses [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 A181.