Age and sex affect αCTLA-4 efficacy alone and combined with αB7-H1 or regulatory T cell depletion in a melanoma model.

Abstract

Abstract Background Most cancer patients are aged but most preclinical studies are in young hosts. We tested age effects on immunotherapy to further our understanding and identify strategies. Methods Young (3 mos) and aged (~26 mos) BL6 mice were injected subcutaneously with syngeneic B16 melanoma cells. 7 days later, mice got 2 μg denileukin diftitox (DD), an FDA-approved IL-2/diphtheria toxin or 200 μg αCD25 (both to deplete Tregs) ± 50 μg αCTLA-4 or 100 μg αB7-H1. 5 days later mice got a 2nd treatment. Results αCTLA-4 depleted intra-tumor Tregs in young but not aged males, a major age effect. In young BL6 males or females αCTLA-4 + αB7-H1 rejected B16 tumors better than either single agent. In aged males, αCTLA4 + αB7-H1 treated B16, but surprisingly accelerated tumors in aged females. Individual agents were effective in young hosts but had negligible effects in the aged. αCTLA-4 + either DD or αCD25 to deplete Tregs significantly reduced tumor growth in young mice but DD was better than αCD25. Neither combo treated B16 in aged mice. This DD dose did not deplete Tregs in aged mice as well as young, but higher DD doses were equally effective. In support, in Foxp3DTR mice, in which we deplete ~100% Treg (versus 20–50% with DD or αCD25), aged mice potently rejected B16. Conclusions Cancer immunotherapy studies in young give an incomplete understanding of clinical effects and mechanisms in the aged most at risk for cancer. We identify major Treg effects and differential Treg depletion efficacy of αCTLA4 and DD contributing to treatment failures in the aged and means to mitigate effects. With appropriate treatments, even very old mice can mount effective anti-tumor immunity. Novel sex differences in aged are unlikely estrogen-related and require further study.