John et al. demonstrated that ectopic expression of B7-family immune checkpoint B7x regulated the Akt–Foxo1 pathway to enhance Foxp3 expression in conventional CD4+ T cells to promote their immunosuppressive capacity and Treg enrichment in the tumor microenvironment, but didn’t increase Treg proliferation. In the syngeneic MC38 tumor model, B7x overexpression reduced the efficacy of anti-CTLA-4 treatment in a Treg-dependent manner. Anti-B7x and anti-CTLA-4 combination led to synergistic therapeutic efficacy and overcame the B7x-mediated resistance to anti-CTLA-4.
Contributed by Shishir Pant
ABSTRACT: Immune checkpoint molecules play critical roles in regulating the anti-tumor immune response, and tumor cells often exploit these pathways to inhibit and evade the immune system. The B7-family immune checkpoint B7x is widely expressed in a broad variety of cancer types, and is generally associated with advanced disease progression and poorer clinical outcomes, but the underlying mechanisms are unclear. Here, we show that transduction and stable expression of B7x in multiple syngeneic tumor models leads to the expansion of immunosuppressive regulatory T cells (Tregs). Mechanistically, B7x does not cause increased proliferation of Tregs in tumors, but instead promotes the conversion of conventional CD4(+) T cells into Tregs. Further, we find that B7x induces global transcriptomic changes in Tregs, driving these cells to adopt an activated and suppressive phenotype. B7x increases the expression of the Treg-specific transcription factor Foxp3 in CD4(+) T cells by modulating the Akt/Foxo pathway. B7x-mediated regulation of Tregs reduces the efficacy of anti-CTLA-4 treatment, a therapeutic that partially relies on Treg-depletion. However, combination treatment of anti-B7x and anti-CTLA-4 leads to synergistic therapeutic efficacy and overcomes the B7x-mediated resistance to anti-CTLA-4. Altogether, B7x mediates an immunosuppressive Treg-promoting pathway within tumors and is a promising candidate for combination immunotherapy.