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.