Kilian and Sheinin et al. demonstrated that MHC-II-restricted antigen presentation on intratumoral blood-borne myeloid (bbm) cells drives cytotoxicity of tumor-reactive CD8+ T cells and response to ICB. Loss of myeloid MHC-II expression led to osteopontin (OPN)-mediated chronic NFAT2 signaling and TOX upregulation, which induced CD8+ T cell dysfunction. Mechanistically, intratumoral MHC class II presentation mediated CD4+ T cell activation, which restricted OPN expression by bbm through IFNγ. In human glioblastoma, reduced MHC-II expression on bbm correlated with increased OPN expression and exhausted intratumoral CD8+ T cell states.
Contributed by Shishir Pant
ABSTRACT: Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8(+) T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4(+) T cells restricts myeloid-derived osteopontin that triggers a chronic activation of NFAT2 in tumor-reactive CD8(+) T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors.