Immunogenic cell death pathway polymorphisms for predicting oxaliplatin efficacy in metastatic colorectal cancer

Abstract

BackgroundImmunogenic cell death (ICD) is a tumor cell death involving both innate and adaptive immune responses. Given published findings that oxaliplatin, but not irinotecan, drives ICD, we investigated whether single nucleotide polymorphisms (SNPs) in the ICD pathway are associated with the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer (mCRC).MethodsTwo randomized clinical trials data were analyzed: discovery cohort, FOLFOX/bevacizumab arm (MAVERICC); validation cohort, FOLFOXIRI/bevacizumab arm (TRIBE); and two control cohorts, FOLFIRI/bevacizumab arms (both trials). Genomic DNA extracted from blood samples was genotyped. Ten SNPs in the ICD pathway were tested for associations with clinical outcomes.ResultsIn total, 648 patients were included. In the discovery cohort, three SNPs were significantly associated with clinical outcomes in univariate analysis: CALR rs1010222 with progression-free survival (G/G vs any A, HR=0.61, 95% CI 0.43–0.88), ANXA1 rs1050305 with overall survival (OS) (A/A vs any G, HR=1.87, 95% CI 1.04–3.35), and LRP1 rs1799986 with OS (C/C vs any T, HR=1.69, 95% CI 1.07–2.70). Multivariate analysis confirmed the trend, but statistical significance was not reached. In the validation cohort, ANXA1 rs1050305, and LRP1 rs1799986 were validated to have the significant associations with clinical outcome. No significant associations of these SNPs were observed in the two control cohorts. Treatment-by-SNP interaction test confirmed the predictive values.ConclusionsThe predictive utility of ICD-related SNPs for the efficacy of oxaliplatin-based chemotherapy was demonstrated, warranting further validation studies to be translated into personalized treatment strategies using conventional cytotoxic agents in mCRC.

Curcumin Suppresses the Progression of Colorectal Cancer by Improving Immunogenic Cell Death Caused by Irinotecan

“…However, up to now, whether IRI can induce ICD remains controversial. A report has shown that although IRI increased the expression of DAMPs, it could not be used as an effective antitumor treatment to protect mice from tumor rechallenge [24]. Consistent with our present findings, previous studies have shown that IRI is a qualified ICD inducer [25, 26].…”

Validation of Genetic Markers Associated with Survival in Colorectal Cancer Patients Treated with Oxaliplatin-Based Chemotherapy

“…Previous studies that focused on a common missense variant GSTP1-rs1695 yielded inconsistent results (19)(20)(21). Variants in other pathways, e.g., drug transport, folate pathway, and VEGF and EGF pathways, immunogenic cell death pathway, enterocyte subtype-related genes, have also been studied without showing concrete evidence of influencing oxaliplatin efficacy (21)(22)(23)(24)(25)(26).…”

Localized Microsphere/Hydrogel for Tumor Immunotherapy of Cardiac Glycoside with Minimal Toxicity

“…Insensitivity to chemotherapeutic agents and postoperative recurrence are the most difficult problems in clinical anticancer treatment, which will lead to the failure of clinical chemotherapy. Growing evidence suggests that chemotherapeutics with both cytotoxic and immunogenic properties (e.g., anthracyclines) are superior to cytotoxic drugs alone (e.g., cisplatin) against the matched patients with several similar tumor characteristics, especially for tumors with low immune infiltrates called “cold tumors” or non-T-cell-inflamed cancers, such as colorectal cancer. , …”

“…Growing evidence suggests that chemotherapeutics with both cytotoxic and immunogenic properties (e.g., anthracyclines) are superior to cytotoxic drugs alone (e.g., cisplatin) against the matched patients with several similar tumor characteristics, especially for tumors with low immune infiltrates called "cold tumors" or non-T-cell-inflamed cancers, such as colorectal cancer. 1,2 Cardiac glycosides (CGs) are an ideal class of multipotent antitumor compounds, although the initial discovery and pharmacological effects are unrelated to oncology. CGs have cytotoxic effects and, more importantly, are capable of converting nonimmunogenic events into bona fide immunogenic cell death (ICD).…”