MARCH 2020
The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Immunotherapy Biomarkers Section Deputy Editor, Kurt A. Schalper, MD, PhD.
“IRF4 instructs effector Treg differentiation and immune suppression in human cancer” by Giorgia Alvisi et al
Intratumoral enrichment and activity of regulatory CD4+ T cells (Tregs) dampen anti-cancer immune responses, possibly limiting the efficacy of immunotherapies. To gain insight into the molecular mechanisms behind increased Treg activity in the tumor microenvironment, Giorgia Alvisi and colleagues used a 27-parameter polychromatic flow cytometry panel to profile T cells from tumors, adjacent cancer-free tissues and peripheral blood in a cohort of 53 treatment-naïve non-small cell lung cancer patients. Compared to other body sites, CD25+Foxp3+ Tregs from tumors were enriched for expression of the transcription factor IRF4. Using cell-surface markers CCR8 and ICOS as a surrogate for IRF4 expression, tumor-derived Tregs were sorted and characterized by RNAseq. Transcriptional signatures for CCR8-ICOS- (i.e. IRF4-) Tregs were characterized by Wnt/beta-catenin and TGF-beta signaling, indicative of quiescence, whereas CCR8+ICO+ (i.e. IRF4+) Tregs displayed a profile characteristic of enhanced metabolic activity and mTORC-1 signaling. Pearson correlation analysis revealed an association between abundant CCR8+ICO+ intratumoral Tregs and higher proportions of CD8+ T cells with features of exhaustion (expressing PD1, TIM3 and TIGIT). T cell-specific deletion of Irf4 significantly slowed tumor growth in mouse models of immunoresponsive colorectal cancer (M38). In human patients, higher ratios of CCR8+ICOS+ Tregs/CD8+ T cells was associated with worse disease-free survival and overall survival for both lung adenocarcinoma and hepatocellular carcinoma.
“CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors” by Haiping Wang et al.
Seeking a target for tumor-specific depletion of regulatory T cells (Tregs) in order to alleviate immunosuppression without causing severe autoimmunity, Haiping Wang et al. characterized metabolic activity and surface marker expression in tumor-derived Tregs as well as peripheral lymphocytes from human breast cancer, lung cancer and melanoma patients as well as two mouse models. Across systems, the fatty acid and oxidized low-density lipoprotein scavenger receptor CD36 emerged as highly expressed specifically in tumor-associated Tregs. Specific deletion of CD36 in Tregs in mouse models of melanoma did not cause any sever systemic inflammatory disorders but did lead to significantly reduced lipid uptake in intratumoral (but not splenic) Tregs, which was accompanied by delayed disease progression and increased frequency of CD8+ tumor-infiltrating lymphocytes, compared to controls. Mitochondrial membrane potential was significantly reduced and profound survival defects in response to lactic acid were observed in CD36-deficient intratumoral Tregs. Genetic ablation of PPAR-beta (a nuclear hormone receptor that responds to lipid signals) in Tregs recapitulated a CD36-definicent phenotype, whereas PPAR-beta agonist treatment rescued tumor growth in mice lacking CD36. Importantly, anti-CD36 monoclonal antibody treatment reduced tumor growth and was additive for the anti-tumor effects of PD-1 blockade in two mouse models of melanoma. The study uncovers a potentially targetable metabolic pathway that contributes to immunosuppression by Tregs in the tumor microenvironment.
“Regulatory T cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis” by Yaqing Zhang et al.
Unexpectedly, given the well-established role played by regulatory T cells (Tregs) in establishing an immunosuppressive tumor microenvironment, Yaqing Zhang and collegues observed accelerated tumor progression after depletion of Tregs in mouse models of spontaneous Kras-driven pancreatic cancer. Notably, Treg depletion failed to elicit a productive anti-tumor response at early or late-stage disease in spontaneous models, whereas depletion was associated with attenuated tumor growth and an increase in cytotoxic CD8+ T cell markers in mice transplanted with syngenic pancreatic cancer cell lines. Regardless of the tumor model, precancerous lesions in Treg-depleted mice displayed identical total numbers of fibroblasts as those in control animals, yet reduced smooth muscle actin staining in the fibrotic microenvironment was observed in animals lacking Tregs. Depletion of T regs in mice with spontaneous pancreatic cancer was associated with a consistent increase in myeloid cells with an immunosuppressive phenotype, including upregulated expression of arginase and programmed death-ligand 1. Flow-sorted epithelial cells and fibroblasts isolated from tumor-bearing pancreata after Treg depletion displayed increased expression of several C-C motif chemokine ligands by RNAseq, and treatment with a commercial CCR1 inhibitor delayed carcinogenesis in the models. The results reveal a complex cross-talk in the pancreas giving rise to compensatory immunosuppression mechanisms that involve multiple cell lineages.