© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. The expression of MHC class II molecules (MHCII) on tumor cells correlates with survival and responsiveness to immunotherapy. However, the mechanisms underlying these observations are poorly defined. Using a murine breast tumor line, we showed that MHCII-expressing tumors grew more slowly than controls and recruited more functional CD4 + and CD8 + T cells. In addition, MHCII-expressing tumors contained more TCR clonotypes expanded to a larger degree than control tumors. Functional CD8 + T cells in tumors depended on CD4 + T cells. However, both CD4 + and CD8 + T cells eventually became exhausted, even in MHCII-expressing tumors. Treatment with anti-CTLA4, but not anti-PD-1 or anti-TIM-3, promoted complete eradication of MHCII-expressing tumors. These results suggest tumor cell expression of MHCII facilitates the local activation of CD4 + T cells, indirectly helps the activation and expansion of CD8 + T cells, and, in combination with the appropriate checkpoint inhibitor, promotes tumor regression.