MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

• DOI: 10.1101/2022.06.10.495502
• Publication Date: 2022-06-13T04:00:13Z
• Authors: Michael Kilian; Ron Sheinin; Chin Leng Tan; Christopher Kraemer; Mirco Friedrich; Ayelet Kaminitz; Khwab Sanghvi; Katharina Lindner; Frederik Cichon; Stafanie Jung; Kristine Jaehne; Miriam Ratliff; Robert Prins; Andreas von Deimling; Wolfgang Wick; Asaf Madi; Lukas Bunse; Michael Platten
• Keywords: 0303 health sciences; 03 medical and health sciences; 3. Good health

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 (MHC) 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 nuclear factor of activated T cells (Nfat)2 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.