Induced MHCII expression on breast cancer cells broadens the responding T cell repertoire, delays tumor-specific T cell exhaustion, and impairs tumor growth

Abstract

Abstract We recently reported that aberrant expression of Major Histocompatibility Class II (MHCII) on human triple negative breast cancer cells correlates with increased tumor infiltrating lymphocytes and prolonged progression free survival. This observation led us to hypothesize that expression of MHCII enhanced the intratumoral CD4+ T cell response, thereby bolstering the tumor-specific CD8+ T cell response, leading to impaired tumor growth. To test this, we transfected the murine breast cancer line TS/A with human class II transcriptional activator (hCIITA) or empty vector, creating MHCII-expressing and MHCII-negative cell lines, respectively. We found that MHCII-expressing tumors grew slower than controls in immunocompetent recipients, but that this difference was abrogated in CD4-depleted and nullified in SCID mice. CD4+ T cells within hCIITA-transfected tumors produced more IFNγ for longer times than those from control tumors. Similarly, CD8+ T cells in MHCII-expressing tumors displayed a more activated phenotype and produced more IFNγ and granzyme B for longer times. Nevertheless, both CD4+ and CD8+ T cells eventually became exhausted in both groups. In addition to boosted effector function, TCR repertoire analysis demonstrated an increase in both breadth and amplitude of T cell response to MHCII-expressing tumors. We next investigated the possibility of inducing MHCII on non-expressing tumors using the histone deacetylase inhibitor Entinostat. Indeed, Entinostat turned on MHCII expression, which correlated with significantly reduced tumor burden. Thus, epigenetic modifiers capable of inducing MHCII expression on tumor cells could avail this augmented T cell response to all patients for enhanced tumor control.</jats:p