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

Stefani Spranger, Robbert M. Spaapen, Yuanyuan Zha, Jason Williams, Yuru Meng, Thanh T. Ha and Thomas F. Gajewski

Sci Transl Med 28 August 2013: Vol. 5, Issue 200, p. 200ra116

Editor's comments:
The ping-pong effect between melanomas cells and reactive T-lymphocytes

There is the concept, that melanoma can be distinguished in subgroups that are recognized by immune reactions and subgroups that are invisible for immune cells. The elegant paper of Spranger et al. now demonstrates that PD-ligand 1, an immunosuppressive molecule expressed by melanoma cells and other immunosuppressive molecules is up-regulated by interferon gamma, secreted by CDA positive T-cells. These data are especially interesting in the context of successful use of anti-PD1 targeted antibodies in advanced melanoma and other cancer types.

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 (Tregs), 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 Tregs, 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.