The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Clinical /Translational Cancer Immunotherapy Associate Editor, Jason J. Luke, MD, FACP.
“Anti-tumour immunity induces aberrant peptide presentation in melanoma” by Osnat Bartok et alProduction of tryptophan metabolites along the kynurenine pathway by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a known mechanism of tumor immune escape, but the effects of prolonged exposure to interferon-gamma on cancer cells remain incompletely understood. Using ribosome profiling on interferon-gamma-treated melanoma cells, Osnat Bartok and colleagues found an unexpectedly high level of stalling of the translation machinery downstream of tryptophan codons, which was associated with an accumulation of frameshifted peptides. Inhibition of IDO1 eliminated the interferon-gamma-induced ribosome stalling downstream of tryptophan codons (referred to as “W-bumps”). Using 2D-LC-MS, 124 out-of-frame and trans-frame peptides not present in any of the in-frame polypeptides (including pseudogenes, alternative mRNA isoforms or upstream open-reading frames) induced by interferon treatment were detected. Reporter constructs designed to detect +1 and -1 frameshifts around tryptophan codons further confirmed the generation of novel peptides with interferon treatment. Secondary structure prediction suggested a role for disorderliness of the nascent peptide after frameshifting in readthrough of tryptophan after interferon treatment. In melanoma cells from patient samples, 94 HLA class I-bound containing out of frame sequences could be detected. Furthermore, co-culture and combinatorial tetramer staining showed that CD8+ T cells were reactive to frameshifted peptides associated with tryptophan read-through. The findings reveal new insight into the interplay between tumor metabolism, immune recognition and adaptive immunity. “Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients” by Erez N Baruch et alGut microbiota are known to influence anti-cancer immune responses, though no specific taxa have been definitively linked to clinical benefit with checkpoint blockade. In a phase I clinical trial including 10 patients with anti-PD-1-resistant melanoma, Erez N Baruch and colleagues show that fecal microbiota transplantation (FMT) is safe and can re-sensitize tumors to checkpoint blockade in some cases. The trial included two FMT donors who had previously received anti-PD-1 monotherapy and achieved complete response lasting one year or more. The 10 trial participants received oral antibiotics (vancomycin and neomycin) for 72 hours prior to FMT, and then donor bacteria were administered via both colonoscopy and oral stool capsules, followed by reinduction of anti-PD-1 therapy (nivolumab) for a total of six combined treatment cycles composed every 14 days until day 90. Three patients achieved objective responses—notably, all three received FMT from the same donor (#1). Two patients showed pseudoprogression before response, and the only adverse events reported were mild arthralgia related to checkpoint blockade and mild bloating linked to FMT. No statistically significant differences in gut microbiota composition pre-treatment were observed among the treated patients. After treatment, however, the group that received FMT from donor #1 had higher relative abundance of taxa including Bifidobacterium adolescentis. Although no significant functional nor metabolic differences were seen within the gut microbiota post-treatment across groups, upregulation of gene sets related to antigen-presenting cells activity, innate immunity, and IL-12 signaling was seen in the intestinal lamina of recipients of FMT from donor #1. Furthermore, FMT from donor #1 was associated with upregulation of multiple immune-related gene sets, including Interferon-gamma signaling, T cell activation, MHC Class II, dendritic cell differentiation, and T helper 1 type immune response. The trial demonstrated that the combination of FMT and retreatment with anti-PD-1 therapy in refractory metastatic melanoma patients was safe and potentially effective, although the characteristics of the donor microbiota that are associated with response remain to be determined. “Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade” by Eduardo Bonavita et alInflammation is a double-edged sword that may support or suppress cancer progression, but the mechanisms by which an inflammatory milieu contributes to tumor immune control or escape remain ill-defined. Eduardo Bonavita and colleagues establish a pivotal role for tumor-derived prostaglandin E2 (PGE2) acting on NK cells in the establishment of immune control and developed an inflammatory gene signature that showed improved predictive power over other putative biomarkers for response to checkpoint blockade across multiple human cancers. The signature was derived using mouse models, where tumors deficient for PGE2 production (via cyclooxygenase (COX)-1 and COX-2 knockout) are controlled by the immune system. Notably, regression did not require intact innate immune signal transducers. While immune elimination of PGE2-deficient tumors did not require neutrophils, depletion of natural killer (NK) cells led to unrestrained tumor growth. In the PGE2-deficient tumors, rejection required CD8+ T cells, and granzyme-B-expressing cell-specific deletion of the PGE2 receptors EP2 and EP4 led to progression. Pathway analysis in tumor-associated macrophages showed higher transcript levels of soluble factors often linked to cancer-promoting inflammation, such as IL-6, CXCL1, CXCL2, IL-1b, and G-CSF in PGE2-competent tumors compared to those lacking PGE2. Upregulation of inflammatory factors associated with cancer inhibition depended on NK cells but did not require Rag1. Pan-tumor analysis of human datasets from The Cancer Genome Atlas showed positive correlations between transcript levels of PTGS2 (which encodes COX-2) and the homologues of the cancer-promoting inflammatory factors in the murine models. Across seven tumor types, stratification based on a COX-2-associated inflammatory signature was independently prognostic, and outperformed other T cell-inflamed tumor-related gene signatures for predicting response to checkpoint blockade. The findings reveal NK-cell driven remodeling of the tumor microenvironment as both a predictive factor for benefit with immunotherapy and a regulator of T cell associated interferon responses.“Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade” by Joseph L Benci et alInterferon gamma plays a paradoxical role in anti-tumor immunity by both enhancing MHC expression and antigen presentation while also enforcing T cell exhaustion. To parse the various effects of interferon signaling in the tumor microenvironment, Joseph L Benci et al created non-overlapping metagenes (defined as the average scaled expression of all genes in a set) for interferon-stimulated genes that have been shown to be associated with resistance to radio- and chemotherapy as well as the hallmark signature of interferon-gamma linked with response to checkpoint blockade. Examined across cell populations in melanoma, the metagene associated with resistance (IFNG.RS) was primarily associated with tumor cells, whereas the interferon-gamma-associated metagene (IFNG.GS) predominated in intratumoral immune cells. In two cohorts of patients with melanoma treated with checkpoint blockade, higher IFNG.GS increased the odds ratio for response, while ISG.RS independently decreased the likelihood, and both were independent of tumor mutational burden (TMB) status. Data from a variety of mouse tumor models with different levels of MHC expression and neoantigen loads suggested that blocking tumor interferon signaling can improve T cell-mediated killing when antigen recognition doesn’t require interferon function. Furthermore, in tumors where blocking interferon signaling compromises T cell-mediated killing, anti-tumor effects of natural killer (NK) and group 1 innate lymphoid cells can compensate to maintain immunity. When PD-L1 levels were fixed, deletion of interferon gamma receptor did not improve anti-CTLA-4 response. Tumor killing after anti-CTLA-4 in the absence of interferon gamma receptor required TRAILR2, and did not depend on antigen presentation by tumor cells themselves. The effects of regulatory T cell depletion and tumor interferon gamma knockout were also non-redundant. In an extended analysis of extended the analysis of previously described exome-sequencing data from non-small cell lung cancer patients receiving checkpoint blockade, the presence of variant in the interferon pathway variants predicted response to therapy independently of TMB and PD-L1 expression. The study comprehensively details oppositional effects of gamma interferon signaling in cancer cells and immune cells that establishes a regulatory balance to limit killing by both arms of the immune system. “Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma” by Anusha Kalbasi et alIntact tumor interferon signaling is a well-known requirement for the success of immune checkpoint blockade therapy, although the direct effects on cytotoxicity of tumor-specific T cells has been less clear thus far. Complementing the work by Joseph L Benci et al, which showed oppositional effects of interferon signaling by tumor and immune cells on the efficacy of checkpoint blockade, here, Anusha Kalbasi and colleagues demonstrate that MHC I expression is necessary and sufficient for effective adoptive cell therapy against interferon signaling-defective cancer cells. In the B16 murine melanoma model, loss of Jak1, but not Jak2, rendered tumors resistant to adoptively-transferred tumor-specific T cells. B16 tumor cells lacking Jak1 did not express MHC class I (MHC I) in vivo, and loss of MHC expression was validated in samples from human patients with melanoma that spontaneously developed JAK1 loss-of-function mutations. In Jak1-defective tumors, forced expression of NLRC5 restored MHC I expression and susceptibility to T cell-mediated killing both in vitro and in vivo. Intratumoral injection of BO-112, a nanoplexed formulation of poly I:C, also overcame loss of Jak1 and restored susceptibility to T cell killing. Not all pattern recognition receptor agonists induced MHC I in the Jak1-deficient tumors—neither lipopolysaccharide nor CpG had an effect, suggesting specificity for double-stranded RNA sensing. Notably, Nlrc5 was not necessary for upregulation of MHC I by BO-112 administration. Instead, transcriptomic data complemented with pharmacologic inhibition and knockdowns revealed that BO-112 induced an “interferon-like” expression signature, including MHC I upregulation, through NF-kappa B signaling. The findings highlight mechanisms that drive resistance to checkpoint blockade but suggest that restoring type I interferon production may be able to overcome that resistance.
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