Interruption of thymic activity in adults improves responses to tumor immunotherapy

Abstract

AbstractThe thymus produces precursors of both effectors and regulatory T cells (Tconv and Treg, respectively) whose interactions prevents autoimmunity while allowing efficient protective immune responses. Tumors express a composite of self- and tumor-specific antigens and engage both Tconv and Treg cells. Along the aging process, the thymus involutes, and tumor incidence increases, a correlation proposed previously to be causal and the result of effector cell decline. In this work, we directly tested whether interruption of thymic activity in adult mice affects Foxp3 expressing Treg composition and function, and alters tumor immune surveillance. Young adult mice, on two different genetic backgrounds, were surgically thymectomized (TxT) and analyzed or challenged 2 months later. Cellular analysis revealed a 10-fold decrease in both Tconv and Treg numbers and a bias for activated cells. The persisting Treg displayed reduced stability of Foxp3 expression and, as a population, showed compromised return to homeostasis upon induced perturbations. We next tested the growth of three tumor models from different origin and presenting distinct degrees of spontaneous immunogenicity. In none of these conditions adult TxT facilitated tumor growth. Rather TxT enhanced the efficacy of anti-tumor immunotherapies targeting Treg and/or the checkpoint CTLA4, as evidenced by increased frequency of responder mice and decreased intra-tumoral Treg to CD8+IFNγ+ cell ratio. Together, our findings point to a scenario where abrogation of thymic activities affects preferentially the regulatory over the ridding arm of the immune activities elicited by tumors, and argues that higher incidence of tumors with age cannot be solely attributed to thymic output decline.