The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Basic Tumor Immunology Section Editor, Cornelis J.M. Melief, MD, PhD.
“Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma” by Catherine S Grasso et al
A deeper understanding of the mechanisms of response and resistance to immune checkpoint blockade therapy could help inform future combinatorial strategies to maximize benefits for patients. Catherine S Grasso and colleagues reveal a central role for interferon gamma signaling in response to checkpoint blockade through bulk RNA-seq analysis of 84 baseline and 85 on-therapy biopsies (including 68 paired samples) from patients with metastatic melanoma in the CheckMate 038 trial who were treated with either single-agent nivolumab or with the combination of nivolumab and ipilimumab. Higher degrees of on-therapy T cell infiltrate increases correlated with clinical response. Response was also associated with higher baseline expression levels of interferon gamma and interferon response genes, which further increased on therapy. In 58 human melanoma cell lines, interferon gamma treatment led to pronounced upregulation of genes involved in antigen presentation as well as chemokines, especially CXCL9, CXCL10, and CXCL11. In biopsies, an increase in on-treatment expression of genes involved in antigen presentation, especially HLA class II, differentiated patients with partial or complete response to therapy from those with progressive or stable disease. Additionally, a response to therapy was correlated with a significant decrease in WNT score (the geometric average of APC, APC2, CTNNB1, MYC, SOX11, SOX2, TCF12, TCF7, and VEGFA). The findings suggest that therapies promoting intratumoral interferon-γ production such as TLR agonists or oncolytic viruses could potentially improve response rates to checkpoint blockade.
“Melanoma Evolves Complete Immunotherapy Resistance through the Acquisition of a Hypermetabolic Phenotype” by Ashvin R Jaiswal et al
Known mechanisms of resistance to immunotherapy, including low mutational burden and loss of components of the antigen presentation machinery, fail to account for the majority of non-responsive cases. Using a model of completely checkpoint inhibitor-refractory melanoma (generated by serial passage in vivo under conditions of CTLA-4, PD-1, and PD-L1 blockade), Ashvin R Jaiswal and colleagues identify a unique “hypermetabolic” phenotype associated with resistance, characterized by coordinated upregulation of the glycolytic, oxidoreductase, and mitochondrial oxidative phosphorylation pathways. Immunotherapy-resistant lines exhibited elevated maximum glycolytic capacity and mitochondrial respiration compared to the parental B16 tumor—a departure from the expected Warburg effect. Resistant tumors had high levels of lactate and other tricarboxylic acid cycle metabolites, which could be visualized in vivo as high rates of pyruvate to lactate conversion via non-invasive MRI. Infiltration of CD8+ T cells into resistant tumors was markedly reduced after checkpoint inhibitor therapy compared to the parental line. The infiltrating CD8+ T cells that were present had reduced glucose uptake and high MitoFM, indicative of minimal effector function. Overexpression of PGAM2, a key enzyme in both glycolysis and synthesis of nucleotide and amino acid precursors, and ADH7, which decreases oxidative stress by reducing NAD to NADH, in melanoma cells led to significant immunotherapy resistance. Single knockouts of PGAM2 and ADH7 each led to increased sensitivity to checkpoint inhibition—the double mutant was not viable. Upregulation of oxidative phosphorylation genes was also observed in a transcriptomic dataset of tumor samples from a cohort of melanoma patients with disease resistance to combined ipilimumab and nivolumab therapy, suggesting that metabolic mechanisms of resistance can have important implications for response to therapy.
“cDC1 Prime and Are Licensed by CD4+ T cells to Induce Anti-Tumor Immunity” by Stephen T Ferris et al
Conventional type 2 dendritic cells (cDC2) are generally considered to be specialized for priming CD4+ T cells, whereas conventional type 1 dendritic cells (cDC1) are thought to perform antigen cross-presentation to prime CD8+ T cells. CD4+ T cells have been proposed to help anti-tumor CD8+ T cell responses by CD40-dependent licensing of antigen-presenting cells, though this has never been formally demonstrated in vivo. Using a variety of conditional deletion models in the setting of help-dependent tumor rejection, Stephen T Ferris et al provide the first in vivo evidence that cDC1-specific CD40 signaling induced by engagement with CD4+ T cells via major histocompatibility (MHC) class II enables optimal CD8+ T cell responses. In two different tumor challenge models, rejection required CD4+ T cells and an absence of cDC1 led to markedly lower early proliferation of antigen-specific CD4+ T cells. Expression of MHC class II on cDC1 was necessary for anti-tumor priming with cell-associated antigens for both CD4+ and CD8+ T cells. Deletion of CD40 in cDC1 did not affect total numbers of antigen presenting cells nor transcriptional signatures. However, CD40 expression in cDC1 (but not cDC2) was required for tumor rejection, and defects in disease control seen with CD40 deletion correlated with reduced expansion of endogenous tetramer-positive CD8+ T cells. The findings upend the prevailing model of initial CD4+ T cells activation by cDC2 and subsequent re-engagement with MHC class II molecules presented by cDC1 for licensing.
“Type 1 Conventional Dendritic Cells Are Systemically Dysregulated Early in Pancreatic Carcinogenesis” by Jeffrey H. Lin et al
Type 1 conventional dendritic cells (cDC1s) are known to be dysregulated in invasive cancer, yet Jeffrey H Lin and colleagues demonstrate the development of systemic cDC1 dysfunction driven by increased apoptosis and causing suboptimal T cell polarization in the earliest stages of preinvasive pancreatic intraepithelial neoplasia (PanIN). Quantification of cDC1 and cDC2 populations (live CD45+CD64−Lin−MHCII+CD11c+ cells, distinguished by XCR1 and SIRPα expression) in the KrasLSL-G12D/+ Trp53LSL-R172H/+ Pdx1-Cre–driven (KPC) mouse model of pancreatic cancer revealed declining abundances of cDC1 intratumorally and in distant tissues early on in the disease course. Reduced frequencies of CD141+ cDC1s were also found in the peripheral blood of human patients with pancreatic ductal adenocarcinoma compared with healthy volunteers. Notably, systemic depletion of cDC1 did not occur in a model of cerulein-induced chronic pancreatitis nor the KrasLSL-G12D/+Trp53fl/fl (KP) mouse model of lung adenocarcinoma. Serum levels of IL-6 and IL-1 beta were higher in KPC pancreatic adenocarcinoma compared to KP lung adenocarcinoma and cerulein-induced chronic pancreatitis. Neutralization of IL-6 with a monoclonal antibody led to rebound and decreased apoptosis of cDC1s, as measured by active cleaved caspase-3. Further supporting apoptosis as the mechanism for cDC1 systemic depletion, bone marrow and peripheral blood pre-cDC1 numbers did not decline over the course of pancreatic cancer progression and Ki-67 levels in lymph node cDC1s were not decreased. Treatment with a CD40 agonist partially rescued cDC1 maturation and function in tumor-bearing mice, measured as induction of type II interferon signaling genes, but failed to increase cDC1 abundance in the tumor microenvironment. Combination treatment with CD40 agonist and Flt3l increased cDC1 abundance in the spleen and tumor, augmented cDC1 expression of MHC II, and enhanced activation of FOXP3−CD4+ T cells in the tumor-draining lymph node. Despite early onset cDC1 dysfunction, the deficits remained reversible, hinting at a rationale for investigation of interventions aimed at promoting the immunogenicity of pancreatic cancers.
“Chemotherapy-Induced Ileal Crypt Apoptosis and the Ileal Microbiome Shape Immunosurveillance and Prognosis of Proximal Colon Cancer” by Maria Paula Roberti et al
Platinum-based chemotherapy is expected to cause immunogenic cell death, potentially enhancing the efficacy of immunotherapy, yet the addition of checkpoint blockade to oxaliplatin has not proven superior to cytotoxic therapy alone for the treatment of microsatellite stable colorectal cancer. Maria Paula Roberti and colleagues reveal new insights into the immunogenicity of chemotherapy in proximal colon cancer, including caspase-3/7-dependent apoptosis of crypt-derived ileal epithelium and adjuvant effects of specific constituents of the microbiota. In tissues collected during right hemicolectomies from patients with proximal colon cancer, oxaliplatin-induced apoptosis was observed only in ileal crypts, but not in the villi, lamina propria or healthy adjacent tissue. Higher baseline levels of cleaved caspase 3 in ileal crypts were associated with favorable prognosis, and ileal apoptosis correlated with the relative abundance of Erysipelotrichaceae while being inversely related to Fusobacteriaceae families. Overrepresentation of Fusobacteriaceae family members was negatively correlated with TIL abundance, and higher relative abundance of B. fragilis predicted long-term survival while other Bacteroides species such as B. uniformis and B. caccae were associated with very poor prognosis. In the MC38 mouse model of MSI-high colon cancer, pre-treatment with broad-spectrum antibiotics reduced the efficacy of oxaliplatin against subcutaneous tumors. In mouse models colonized with proximal colonic content from colon cancer patients, 4 out of 12 microbiota tested induced complete resistance to oxaliplatin. Response to oxaliplatin was accompanied by increased colonization with B. fragilis and an increase in ICOS-expressing CXCR5hi PD-1hi CD4+ TFH cells in tumor-draining lymph nodes. Immunization with a vaccine comprised of non-malignant ileal epithelial cells collected from oxaliplatin-treated mice led to reduced MC38 tumor growth—functional caspase3/7 was required in donor mice for efficacy, as were TFH cells in recipients. Vaccination with sterile ileal epithelial stem cell-derived organoids accelerated MC38 progression, but supplementation with microbiota from 6 of 10 patients could restore anticancer effects as could concurrent administration of recombinant IL-1β. Notably, and potentially of interest for future microbiome-based biomarkers to predict response to immunotherapy, colonization of tumor-bearing mice with B. fragilis or E. ramosum improved disease control for oxaliplatin combined with PD-1 blockade, while P. clara or F. nucleatum impaired efficacy of the combination regimen.
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