The T-cell oxygen sensing machinery generates immunologic tolerance in the lung.
Major finding: The T-cell oxygen sensing machinery generates immunologic tolerance in the lung.
Mechanism: Oxygen binds to PHD proteins to control T-cell differentiation programs via repression of HIF1α.
Impact: Inhibition of T cell–intrinsic oxygen sensing may be a potential cancer immunotherapy strategy.
Successful metastatic colonization is mediated by the interactions between disseminated tumor cells and the metastatic niche. Although the tumor type of the primary cancer influences organotropic metastasis, certain organs, such as the lungs and liver, are the most common sites of metastasis, suggesting that the formation of local metastatic niches may be dictated by tissue-specific physiology, such as the local immune response. Coordination of the effector T cell (Teff)–mediated immune response and of the regulatory T cell (Treg)–mediated control of the inflammatory response is crucial in the lung, which is continuously exposed to nonpathogenic foreign antigens. Clever and colleagues interrogated the role of the oxygen-sensing prolyl hydroxylase domain containing (PHD) family of proteins, which is expressed by T cells and targets hypoxia-inducible factor-1α (HIF1α) and HIF2α for proteasomal degradation in an oxygen-dependent manner, in T-cell differentiation and function in the lung metastatic niche. Selective depletion of PHD2, PHD1, and PHD3 proteins in CD4+ and CD8+ T cells in mice (PHD-tKO mice) revealed that in the lung, PHD proteins function redundantly to subdue Teff function and mute the CD4+ T helper cell 1 (Th1) inflammatory response to nonpathogenic foreign antigens. Further, PHD proteins were shown to concomitantly promote induced Treg (iTreg) differentiation and inhibit Th1 differentiation in the presence of oxygen. Circulating murine melanoma cells formed fewer lung tumors in PHD-tKO mice compared to wild-type mice, and treatment with a hypoxia mimetic improved adoptive T-cell transfer immunotherapy against both subcutaneous and pulmonary murine melanoma. Mechanistically, PHD proteins mediated the oxygen-dependent repression of HIF1α accumulation to restrain glycolysis, which resulted in increased iTreg differentiation and the complete loss of Th1 differentiation to form immunologically tolerant metastatic niches in the lung. Together, these results describe the site-specific mechanism underlying the generation of an immunologically favorable microenvironment in the lung that promotes the outgrowth of disseminated tumor cells.