Tumors Can Co-Opt Naturally Occurring Organ-Specific Tregs

Tumors can avoid detection by the immune system by recruiting regulatory T cells (Treg), an immunosuppressive T-cell subpopulation that normally acts to prevent autoimmune diseases and maintain immune homeostasis. The presence of Tregs in the tumor microenvironment is associated with poorer patient outcomes, and Treg depletion potentiates antitumor immune responses in preclinical cancer models, suggesting that targeting tumor-associated Tregs may have clinical benefit. However, the origin and function of tumorinfiltrating Tregs are poorly understood, which may hinder efforts to develop immunomodulatory cancer therapies. Malchow and colleagues fingerprinted tumor-infiltrating Tregs in a mouse model of prostate cancer by sequencing the T-cell antigen receptor alpha (TCRα) chain in T-cell populations expressing FOXP3, a Treg marker. An identical TCRα chain was recurrently found in Tregs within the prostate tumors, suggesting that tumor-infiltrating Tregs can arise from a single clone. Furthermore, Tregs expressing this TCRα chain were only found within the prostate tumors and prostate-draining lymph nodes, indicating that these Tregs were expanded locally, not systemically. Interestingly, the TCRα repertoires of Tregs isolated from different tumors were highly similar but distinct from those of effector CD4⁺ T cells, which can be converted de novo into Tregs. The authors generated transgenic mice expressing this specific TCRα chain and found that the corresponding Tregs accumulated in the prostates of tumor-free mice, establishing that the Tregs did not recognize a tumor-specific antigen but a self-antigen expressed in the tissue of cancer origin. Although it remains unclear whether these prostate-resident Tregs suppress antitumor immune responses and whether tissue-specific Tregs are found in other cancer types, these results provide support for a model in which tumors recruit preexisting Tregs reactive to self-antigens to induce organ-specific immune tolerance.

Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 2013;339:1219–24.

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