Abstract 3086: Decoding the intimate dialogues between stem cells and immune cell for cancer immunotherapy

Adult stem cells (SCs) reside in various body sites where they govern tissue homeostasis and orchestrate wound repair. As a group of long-lived and indispensable cells, they inevitably face the challenge of experiencing repeated bouts of inflammation initiated by tissue injury, or infection. Recently, a subset of TGF-β-reactive tumor-initiating cells were found at the tumor-stroma interface of in skin or head & neck squamous cell carcinomas (SCC). These cells appear to be enriched with adult stem cells features. To prevent collateral damage from immune reactions in normal tissue or to drive oncogenic progression, it is essential for SCs or tumor initiating SCs (tSC) to develop unique capacity to adapt to inflammation. However, so far, it is still unclear how stem cells achieve immune adaptation. In order to explore this question, we designed a novel mouse model for spontaneous skin SCC that could be effectively challenged with adoptive T cell transfer (ACT)-based immunotherapy. Importantly, we genetically coupled the targeted antigen and HRASG12V, so that the tumors grown on these mice cannot easily silence the presentation of targeted antigen and upon ACT treatment, these tumors rapidly regress. Remarkably, singe cell RNA-seq followed by genetic lineage tracing revealed the ACT survivors were a group of TGFβ-responding tSCs. To determine the SC-specific programs that could be hijacked by cancer to drive immune evasion, we profiled these ACT-surviving tSCs, as well as normal hair follicle stem cells (HFSCs) that are isolated from highly inflammatory condition, such as a cutaneous wound. Surprisingly, in both normal SCs and tSCs, we observed activation of class II MHC and CD80, the immune modulatory molecules canonically found on antigen-presenting immune cells. To test the functional significance of these proteins for epithelial SCs, CD80 was ablated by designing an in vivo CRISPR gene editing strategy. Interestingly, when we profiled the immune composition of Cd80 cKO wound or tumor, we observed significant reduction in regulatory T cells (Treg), resulting drastic accumulation of neutrophils in the wounds of Cd80 cKO mice, or antigen-specific cytotoxic T cells in the skin SCC. Cancer and wounds share many characteristics, and cancer has been considered as “a wound that never heals”. Prior interpretations mainly pointed to the observations that similar molecular pathways drive stem cell proliferation, differentiation and stress responses in both wound and cancer. The intimate dialogue between stem cells and surrounding immune cells has long been overlooked. In this study, we have unveiled that the stem cell-immune cell crosstalk actually dictates the outcomes of successful tissue regeneration and this mechanism can be hijacked by cancer to survive from immunotherapy treatment. These discoveries will provide a new revenue to leverage and target these vital dialogues as novel cancer immunotherapy. Citation Format: Cynthia Truong, Weijie Guo, Alexandrer Rudensky, Elaine Fuchs, Yuxuan Phoenix Miao. Decoding the intimate dialogues between stem cells and immune cell for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3086.