MHC-II neoantigens shape tumor immunity and response to immunotherapy

Abstract

The ability of the immune system to eliminate and shape the immunogenicity of tumors defines the process of cancer immunoediting ¹ . Immunotherapies such as those that target immune checkpoint molecules can be used to augment immune-mediated elimination of tumors and have resulted in durable responses in cancer patients that did not respond to previous treatments. However, only a subset of patients benefit from immunotherapy and more knowledge about what is required for successful treatment is needed ^{2– 4} . While the role of tumor neoantigen-specific CD8 ⁺ T cells in tumor rejection is well established ^{5– 9} , the roles played by other T cell subsets have received less attention. Here we show spontaneous and immunotherapy-induced anti-tumor responses require the activity of both tumor antigen specific CD8 ⁺ and CD4 ⁺ T cells, even in tumors that do not express MHC class II. Additionally, tumor cell expression of MHC class II-restricted antigens is required at the site of successful rejection, indicating that CD4 ⁺ T cell activation must also occur in the tumor microenvironment. These findings suggest that MHC class II-restricted neoantigens have a key function in the anti-tumor response that is nonoverlapping with that of MHC class I-restricted neoantigens and therefore need to be considered when identifying patients who will most benefit from immunotherapy.