Up-Regulation of PD-L1, IDO, and T _regs in the Melanoma Tumor Microenvironment Is Driven by CD8 ⁺ T Cells

TLDR

Tumor escape is linked to immunosuppressive mechanisms that inhibit T‑cell activation, and even tumors with CD8⁺ T‑cell infiltration are not rejected. The study demonstrates that T‑cell‑inflamed tumors exhibit high levels of IDO, PD‑L1, and FoxP3⁺ Tregs, indicating these inhibitory pathways act as negative feedback following CD8⁺ T‑cell infiltration. In mouse models, CD8⁺ T cells drive IDO and PD‑L1 up‑regulation via IFN‑γ and recruit Tregs through CCR4‑binding chemokines and induced proliferation. These results show that the immune system, not cancer cells, orchestrates these suppressive pathways, suggesting checkpoint inhibitors may be most effective in patients with preexisting T‑cell‑inflamed tumors.

Abstract

Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8(+) T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejected. In the current report, we show that it is the subset of T cell-inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3(+) regulatory T cells (T(regs)), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8(+) T cell infiltration. Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of T(regs), in the tumor microenvironment depended on the presence of CD8(+) T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation. Our results argue that these major immunosuppressive pathways are intrinsically driven by the immune system rather than being orchestrated by cancer cells, and imply that cancer immunotherapy approaches targeting negative regulatory immune checkpoints might be preferentially beneficial for patients with a preexisting T cell-inflamed tumor microenvironment.