Description

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

Tyler R. McCaw*¹; Selene Meza-Perez¹; Mei Li²; Donald J. Buchsbaum²; Dmytro Starenki³; Sara Cooper³; Andres Forero¹; Troy D. Randall¹

¹Department of Medicine, Univ. of Alabama at Birmingham, Birmingham, AL; ²Department of Radiation Oncology, Univ. of Alabama at Birmingham, Birmingham, AL; ³HudsonAlpha Institute for Biotechnology, Huntsville, AL

*Corresponding author

We recently reported Major Histocompatibility Class II (MHCII) expression on human triple negative breast cancer cells correlates with prolonged progression-free survival and increased tumor infiltrating lymphocytes. We hypothesized that expression of MHCII enhanced the intratumoral CD4+ T cell response, thereby bolstering the tumor-specific CD8+ T cell response. To test this we transfected murine breast cancer (TS/A) cells with the human MHCII transcriptional activator (hCIITA) or empty vector, injected transfected cells into BALB/c mice, and analyzed the evolving immune response. We found hCIITA-expressing tumors grew much slower than controls in immunocompetent mice, but this difference was nullified in immunocompromised and markedly reduced in CD4+ T cell depleted mice. CD4+ T cells isolated from hCIITA-transfected tumors produced more IFNγ, IL-17A, and surprisingly granzyme B for longer times than their counterparts in control tumors. Similarly, CD8+ T cells from hCIITA-transfected tumors were more activated and produced more IFNγ and granzyme B for longer times. Nevertheless, both CD4+ and CD8+ T cells eventually became exhausted in both groups. TCR repertoire analysis showed both the breadth and magnitude of expansion of responding clones were increased in hCIITA-transfected tumor infiltrating T cells. Collectively, these results suggest that expression of MHCII on tumor cells promotes local CD4+ T cell effector functions, enhancing CD8+ T cell responses and delaying T cell exhaustion. Thus, epigenetic modifiers, like histone deacetylase inhibitors, that induce MHCII expression on tumor cells will likely benefit anti-tumor immune responses.