- Bakhru, Pearl;
- Zhu, Meng-Lei;
- Wang, Hsing-Hui;
- Hong, Lee K;
- Khan, Imran;
- Mouchess, Maria;
- Gulati, Ajay S;
- Starmer, Joshua;
- Hou, Yafei;
- Sailer, David;
- Lee, Sandra;
- Zhao, Fengmin;
- Kirkwood, John M;
- Moschos, Stergios;
- Fong, Lawrence;
- Anderson, Mark S;
- Su, Maureen A
Blockade of immune checkpoint proteins (e.g., CTLA-4, PD-1) improves overall survival in advanced melanoma; however, therapeutic benefit is limited to only a subset of patients. Because checkpoint blockade acts by "removing the brakes" on effector T cells, the efficacy of checkpoint blockade may be constrained by the limited pool of melanoma-reactive T cells in the periphery. In the thymus, autoimmune regulator (Aire) promotes deletion of T cells reactive against self-antigens that are also expressed by tumors. Thus, while protecting against autoimmunity, Aire also limits the generation of melanoma-reactive T cells. Here, we show that Aire deficiency in mice expands the pool of CD4+ T cells capable of melanoma cell eradication and has additive effects with anti-CTLA-4 antibody in slowing melanoma tumor growth and increasing survival. Moreover, pharmacologic blockade of central T cell tolerance and peripheral checkpoint blockade in combination enhanced antimelanoma immunity in a synergistic manner. In melanoma patients treated with anti-CTLA-4 antibody, clinical response to therapy was associated with a human Aire polymorphism. Together, these findings suggest that Aire-mediated central tolerance constrains the efficacy of peripheral checkpoint inhibition and point to simultaneous blockade of Aire and checkpoint inhibitors as a novel strategy to enhance antimelanoma immunity.