Androgen receptor mediated suppression of CD4 T cell anti-tumor immunity 3870

Description CD4 T cells are essential for effective immune responses, but their activity is suppressed by various stimuli, including steroid hormones like glucocorticoids. The impact of other steroids such as androgens on CD4 T cells has been described in regulatory T cells and in allergy, but less is known in the context of cancer. This knowledge gap may present a critical barrier to improving immunotherapy. In this study, we demonstrate that deletion of the androgen receptor (Ar) in CD4 T cells reduces tumor growth and enhances CD4 infiltration into the tumor microenvironment (TME). To examine AR signaling in CD4 T cells without confounding effects from global androgen modulation, we developed a CD4-specific Ar knockout (ARKO) mouse model using a CD40lgcre crossed with an exon 2 Ar floxed mouse. We observed no gross differences in T cell development in the thymus or periphery of CD4 ARKO mice. However, functional differences in ARKO CD4 T cells were evident in the TME. In mixed chimeras, where ARKO and WT CD4 T cells directly competed, ARKO CD4 T cells accumulated more frequently in the TME, a trend not observed in other tissues. Furthermore, the ratio of conventional to regulatory T cells was increased in ARKO CD4 T cells in the TME. These findings suggest that Ar is dispensable for CD4 T cell development but regulates activation and/or trafficking to sites of inflammation. We propose that Ar has a suppressive impact on CD4 T cells that can be leveraged to improve anti-tumor immunity.