Two major categories of melanoma metastases have been observed based on gene expression profiling and confirmatory technologies. One subgroup of patients has T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN gene signature. In contrast, the other major subset lacks this phenotype and these tumors show a behavior of immune “exclusion”. The optimal immunotherapeutic intervention may be distinct for these two general subsets. The T cell-inflamed tumor microenvironment subset contains the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3+ Tregs, and evidence for T cell-intrinsic anergy has also emerged. In addition, the mechanism of induction of these inhibitory mechanisms has been elucidated—PD-L1 and IDO are induced by IFN-γ, and Tregs are largely recruited by chemokines such as CCL22, produced by activated CD8+ effector T cells. Preclinical experiments have confirmed a critical role for all 4 of these mechanisms in limiting anti-tumor T cell efficacy in vivo, giving a mechanism base for translation back into the clinic. These include anti-PD-1/PD-L1 mAbs, IDO inhibitors, and approaches to deplete CD25+ Tregs and/or reverse anergy. The presence of multiple inhibitory mechanisms in the same tumor microenvironment argues that combination therapies may be advantageous to overcome compensatory effects. Preclinical data indicated synergy between anti-CTLA-4 +/- anti-PD-L1 +/- IDO inhibition. The mechanism of synergy is striking, as it correlates with a marked improvement of IL-2 production and proliferation of tumor-infiltrating CD8+ T cells. Clinical translation of these combination immunotherapies is promising and ongoing. In contrast to the T cell-inflamed melanomas, a new paradigm may be needed to promote de novo inflammation in cases of the non-T cell-infiltrated tumor microenvironment. Recent work has indicated that successful innate immune sensing of tumors involves the STING pathway and type I IFN production. Therefore, STING agonists are being developed to promote effective innate immune activation and generation of an adaptive immune response. Molecular mechanisms that explain the presence or absence of a T cell-inflamed tumor microenvironment in patients are being elucidated, which is opening up new concepts for therapies that may overcome immune exclusion and render patients responsive to immunotherapies.
Citation Format: Thomas Gajewski. Molecular mechanisms controlling the T cell-inflamed tumor microenvironment: Implications for therapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA09.
- ©2015 American Association for Cancer Research.