The Journal for ImmunoTherapy of Cancer (JITC), the official journal of the Society for Immunotherapy of Cancer (SITC), is a leading publication of original research articles, literature reviews, position papers and discussion on all aspects of tumor immunology and cancer immunotherapy–from basic research to clinical application.
To provide JITC readers with a well-rounded view of research in tumor immunology and cancer immunotherapy, JITC editors (view the JITC Editorial Board here) will share a monthly reading list of publications in other journals that have their attention and add value to what readers may find in JITC.
The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Clinical/Translational Cancer Immunotherapy Section Editor, Douglas G. McNeel, MD, PhD.
“Interferon-Induced IDO1 Mediates Radiation Resistance and Is a Therapeutic Target in Colorectal Cancer” by Baosheng Chen et al
Radiation is a primary or adjunctive therapy for locally advanced sporadic and colitis-associated colorectal cancer and the PI3K/AKT pathway has been shown to promote radioresistance. Building on prior work demonstrating that IDO1 activates PI3K/AKT signaling, Baosheng Chen and colleagues establish IDO1 blockade as a promising potential adjuvant therapy to radiation in multiple pre-clinical models. Radiation treatment was associated with elevated IDO1 expression across several murine and human colorectal cancer cell lines (regardless of MSI status) as well as patient samples. IDO1 expression after radiation was attenuated by blockade of the common type 1 interferon alpha/beta receptor in both cultured cells and xenograft models. Treatment with an anti-interferon gamma antibody had no effect in vitro, but did significantly reduce IDO1 mRNA levels after irradiation in engrafted tumors. A combination of radiation and the highly specific IDO1 inhibitor epacadostat halted tumor growth in vivo and caused higher rates of apoptosis (measured by cleaved caspase-3 and TUNEL) and lower proliferation rates (measured by Ki67) in cancer cells from treated animals compared to untreated controls or either monotherapy. Radiotherapy monotherapy induced an unfavorable low ratio of cytotoxic CD8+ to regulatory Fox3P+ T cells (Tregs) as well as a mixed profile of inflammatory and immunosuppressive cytokines. Conversely, combination radiotherapy and epacadostat promoted a favorable elevated CD8+ to Treg ratio and high levels of inflammatory cytokines including IL15, TNF alpha, interferon gamma, macrophage inflammatory proteins and CCL5. Importantly, IDO1 blockade was protective of normal small intestinal epithelium crypts in standard single-dose radiation assays of crypt survival and apoptosis in organoids and, in vivo, epacadostat hastened weight rebound in mice treated with fractionated abdominal radiation.
“PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer” by Brian Diskin et al
Immunosuppressive PD-L1 upregulation on tumor cells has formed the basis for several successful immunotherapies, however the significance of PD-L1 expression by T cells remains poorly understood. Brian Diskin et al. demonstrate elevated PD-L1 expression on T cells in tumor-infiltrating lymphocytes and peripheral blood mononuclear cells in samples from human patients with pancreatic ductal adenocarcinoma (PDA). In mouse models of PDA, conditional deletion of PD-L1 in T cells led to smaller tumors compared to controls. Ligation of T cell PD-L1 prevented CD8+ T cell priming, attenuated antigen-restricted CD4+ T cell activation and inhibited activation and proliferation. Global transcriptomic changes in T cells were observed upon PD-L1 ligation including downregulation of interferon gamma signaling-associated genes. Transfer of PD-L1+ T cells into mouse models of PDA resulted in larger tumors and inhibition of cytotoxic T cell activation as well as antigen-restricted CD4+ T cell proliferation. Additionally, PD-L1 engagement promoted an M2-like phenotype in macrophages, with upregulation of of STAT6 and Akt signaling upon co-culture with PD-L1+ T cells. Adoptive transfer of PD-L1+ T cells also led to M2-polarization of tumor-associated macrophages in vivo. The findings reveal pleiotropic effects of PD-L1 expression on both innate and adaptive immune tolerance in cancer.
“An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors” by Katharina Reinhard et al
Despite achieving remarkable and durable responses in the treatment of B-cell malignancies, multiple challenges have impeded successful use of chimeric antigen receptor (CAR) T cells for the treatment of solid tumors including limited cancer-specific antigens and poor persistence of infused cells. Katharina Reinhard et al identify the developmentally regulated tight junction protein claudin 6 (CLDN6) as a potential CAR target in solid tumors and introduce a nanoparticulate RNA vaccine for systemic delivery of the antigen in order to promote expansion of adoptively transferred cells. In both mice and humans CLDN6 was shown to be broadly expressed in fetal organs and downregulated to undetectable levels in adults. T cells transfected with a second-generation CLDN6-CAR with a 4-1BB costimulatory domain recognized and lysed of CLDN6-expressing cells in vitro, even at the lowest target level. In immunodeficient mice with large ovarian tumors, a single dose of CLDN6-CAR T cells led to complete tumor regression within two weeks and detectable persistence of the adoptively transferred cells for a full 25 days after infusion. Immunocompetent mice injected intravenously with nanoparticulate RNA vaccine (CLDN6-LPX), developed detectable CLDN6 surface expression on splenic dendritic cells and macrophages with strong activation of natural killer (NK), B, and T cells in the spleen and lymph nodes. In mice that received CLDN6-CAR T cells, subsequent vaccination with CLDN6-LPX led to a rapid amplification of multiple orders of magnitude, even in animals that received sub-therapeutic doses. Additional CLDN6-LPX treatments maintained CAR T cells at a high level, and although the frequencies of engrafted cells declined during extended treatment-free intervals, the numbers rapidly re-expanded with each additional vaccination and never dropped to baseline levels and instead stabilized at a roughly 10-fold higher frequency. The results offer a foundation for overcoming some of the limitations for CAR T cells in the treatment of solid tumors.
“MicroRNAs in Tumor Exosomes Drive Immune Escape in Melanoma” by Virginie Vignard et al
MicroRNAs (miRNAs) regulate more than 60% of human genes and they are known to act as both tumor suppressors and oncogenes in cancers. Virginie Vignard et al. provide evidence that melanoma-derived miRNAs packaged and secreted in extracellular vesicles inhibit cytokine production and antigen receptor signaling in T cells. Through two complementary analyses, 250 miRNAs were identified as enriched in melanoma exosomes. Uptake of melanoma-derived exosomes was observed through both fluorescence and electron microscopy, and internalization required both energy and a functioning actin cytoskeleton. CD8+ T cells exposed to melanoma exosomes showed significantly reduced tumor necrosis factor alpha (TNFalpha) production, though IL-2 and interferon gamma secretions were unaffected. Using target enrichment analysis and the public GSE35387 data set hsa-miR-122, hsa-miR-3187-3p, hsa-miR-498, hsa-miR-149, and hsa-miR-181 were identified as miRNAs that potentially target genes involved in T cell immune response that are also enriched in melanoma-derived exosomes. All candidate miRNAs caused a significant reduction in TNFalpha secretion when transfected into CD8+ T cells, and hsa-miR-498 was confirmed to interact with the 3’UTR of the TNFalpha gene through luciferase assays. Similarly, CD8+ T cells substantially downregulated expression of CD45, which is vital for successful antigen receptor signaling. When transfected into T cells, two exosome-enriched miRNAs, hsa-3187-3p and hsa-miR-49, decreased CD45 expression by 18% and 14%, respectively. Only hsa-3187-3p was detected as interacting with the 3’ UTR of PTPRC (the protein-coding gene for CD45) through luciferase assays. The findings reveal a new paradigm through which melanoma suppresses effective anti-tumor T cell responses.
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