Assistant Professor Massachusetts General Hospital Boston, Massachusetts, United States
Abstract Text: T cell inflamed, “hot” tumors are known to respond better to immunotherapy compared to T cell non-inflamed “cold” tumors. However, defining cancer cell-intrinsic features that portend “hot” versus “cold” tumor microenvironments has proven challenging. Here we developed 2 novel mouse cancer models, generated from the same tumor, which display contrasting “hot” (BBNF2) and “cold” (BBNF9) tumor phenotypes. Co-implantation of tumors resulted in dominant immune suppression levied by immune “cold” tumors. Comparative analysis of these tumors identified that cancer cell-intrinsic expression of ALDH1 was selectively associated with immune “cold” tumors. BBNF9 tumors had low T cell infiltration and diminished dendritic cell (DC) responses. Treatment of DCs with retinoic acid (RA) the main metabolite from ALDH1 enzymatic activity, could suppress DC responses. DC-specific deletion of Retinoid X receptor alpha (RXRa), a key receptor mediating sense of RA, rendered DCs insensitive to RA-mediated suppression, and enhanced DC IL-12 production. Cancer cell-specific deletion of ALDH1 resulted in reduced tumor neutrophil infiltration, enhanced DC response, and slower tumor growth. Collectively, we find that cancer-cell intrinsic ALDH1 confers immune evasive properties to cancers by engaging a neutrophil axis and suppressing antigen presentation.
