Tumor-Intrinsic Mediators of T Cell-Inflamed Versus Non-Inflamed Tumor Microenvironment
Thomas F. Gajewski
University of Chicago, Chicago, IL, USA
Checkpoint blockade immunotherapy is having a major therapeutic impact in a wide range of cancers types, but only a minority of patients respond overall.Clinical activity is favored in patients having a T cell-inflamed microenvironment at baseline, which has generated fundamental questions regarding the factors that regulate the endogenous T cell response against cancer.The T cell-inflamed tumor phenotype includes immune inhibitory factors including PD-L1/PD-1 interactions, expression of IDO, and infiltration with Tregs, which is consistent with the notion that checkpoint blockade immunotherapy is restoring functional efficacy of CD8+ T cells already in the tumor.Mouse mechanistic studies and human correlative analyses have indicated that innate immune sensing of tumors involves the host STING pathway, type I IFN production, and cross-priming of T cells via Batf3 DCs.New strategies are being developed to engage or mimic this pathway as a therapeutic endeavor, including novel STING agonists.The molecular mechanisms that mediate the absence of the T cell-inflamed tumor microenvironment are being elucidated using parallel genomics platforms studying tumor, germline DNA, and commensal microbiota correlates.The first tumor-intrinsic oncogene pathway identified that mediates immune exclusion is the Wnt/β-catenin pathway, which argues that new pharmacologic strategies to target this pathway should be developed.Interestingly, the mechanism of immune evasion involves lack of recruitment and activation of Batf3 DCs.β-catenin-expressing tumors also are resistant to adoptive T cell therapy in mouse models, because of failed recruitment of CD8+ effector cells into the tumor microenvironment.Evidence is accumulating that additional tumor cell-intrinsic genetic aberrations may also contribute to immune escape, including alterations in c-myc, FGFR3, and PTEN.The paradigm that targeted inhibitors of these specific pathways might restore immune cell infiltration and expand immunotherapy efficacy is currently being investigated.Host factors also are being identified that contribute to the degree of endogenous immune cell infiltration, including germline SNPs and the composition of the commensal microbiota.These results suggest that ultimately, an integrated multidimensional genomic/bioinformatic approach may have the greatest value as a composite predictive biomarker for immunotherapy efficacy, as well as to identify patient-specific interventions for improving clinical outcomes further.
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