Tumor-specific CD4⁺ T cells have been shown to mediate efficient antitumor immune responses against cancer. Such responses can occur through direct binding to MHC class II (MHC II)-expressing tumor cells, or indirectly via activation of professional antigen-presenting cells (APC) that take up and present the tumor antigen. We have previously shown that CD4⁺ T cells reactive against an epitope within the Ig light chain variable region of a murine B-cell lymphoma can reject established tumors. Given the presence of MHC II molecules at the surface of lymphoma cells, we investigated whether MHC II-restricted antigen presentation on tumor cells alone was required for rejection. Variants of the A20 B lymphoma cell line that either secreted or intracellularly retained different versions of the tumor-specific antigen revealed that antigen secretion by the MHC II-expressing tumor cells was essential both for the priming and effector phase of CD4⁺ T-cell-driven antitumor immune responses. Consistent with this, genetic ablation of MHC II in tumor cells, both in the case of B lymphoma and B16 melanoma, did not preclude rejection of tumors by tumor antigen-specific CD4⁺ T cells in vivo These findings demonstrate that MHC class II expression on tumor cells themselves is not required for CD4⁺ T-cell-mediated rejection and that indirect display on host APC is sufficient for effective tumor elimination. These results support the importance of tumor-infiltrating APC as mediators of tumor cell killing by CD4⁺ T cells.Significance: Elimination of tumors by CD4⁺ T cells recognizing secreted tumor neoantigens can occur in the absence of tumor cell-intrinsic MHC II expression, highlighting the potential clinical relevance of indirect antigen recognition by tumor-infiltrating APC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4573/F1.large.jpg Cancer Res; 78(16); 4573-85. ©2018 AACR.

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