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Catenin Alpha-2 Mutation Changes the Immune Microenvironment in Lung Adenocarcinoma Patients Receiving Immune Checkpoint Inhibitors.

ABSTRACT: Background: Lung cancer has always been the most prevalent cancer. Lung adenocarcinoma (LUAD) is the most common lung cancer subtype and has a high tumor mutation rate. In addition to KRAS, EGFR, ALK, HER2, ROS1, and BRAF, which are known to have high mutation rates, we discovered some new mutated genes, such as catenin alpha-2 (CTNNA2), in LUAD patients treated with immune checkpoint inhibitors (ICIs). These mutant genes are potential therapeutic targets for LUAD. Methods: We analyzed a cohort of LUAD patients with somatic mutation and survival data in the Cancer Genome Atlas (TCGA) database and a cohort of LUAD patients receiving immune checkpoint inhibitors with clinical data and whole-exome sequencing (WES) mutation data to evaluate the role of CTNNA2 gene mutation in LUAD. In addition, CIBERSORT was used to analyze the immune characteristics of CTNNA2 wild-type patients and CTNNA2 mutant-type patients, and gene set enrichment analysis (GSEA) was employed for pathway enrichment analysis. The results were verified by downloading data regarding the drug sensitivity of LUAD cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) database. Results: We found that CTNNA2 mutation was associated with longer overall survival (OS) in LUAD patients. Analysis of the cohort from the Cancer Genome Atlas showed that patients with CTNNA2 mutation had more tumor neoantigens and a greater tumor mutation burden (TMB). Through further analysis of the tumor immune microenvironment, we found that in LUAD patients with CTNNA2 mutations, the gene expression levels of chemokine C-X-C motif chemokine 9 (CXCL9) and granzyme B (GZMB) were elevated, and the gene expression level of inhibitory receptor killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) was significantly reduced. These alterations might affect gene expression in macrophages, NK cells, and mast cell markers. In addition, LUAD patients with CTNNA2 mutation had a significantly increased number of mutations in DNA damage response (DDR) genes. The drug susceptibility results and gene set enrichment analysis showed that after CTNNA2 mutation occurred, changes were found in the DNA damage response pathway, the phosphoinositide 3-kinase (PI3K) pathway and others, indicating that CTNNA2 mutation can regulate the activation of PI3K and DDR pathways. Conclusion: Our findings provide novel insights into the underlying pathogenesis of LUAD. CTNNA2 mutation can change the immune microenvironment, thereby improving patient prognosis. The results also suggest that CTNNA2 may become a new biomarker and therapeutic target for LUAD in the future.

SUBMITTER: Wen Y

PROVIDER: S-EPMC8215613 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Influenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs. METHODS:Patients on ICIs who developed myocarditis (n?=?101) (cases) were compared to ICI-treated patients (n?=?201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6?months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death. RESULTS:The FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p?=?0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p?=?0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p?=?0.10) including lower rates of pneumonitis (12 vs. 36%, p?=?0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p?=?0.002). CONCLUSION:The rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.

Project description:BackgroundHyponatremia due to endocrinopathies such as adrenal insufficiency and hypothyroidism has been reported in patients receiving immune checkpoint inhibitors (ICIs). We determined the risk and predictors of hyponatremia and other electrolyte abnormalities in a 'real-world' sample of patients receiving ICIs to treat advanced malignancies.MethodsThis was a retrospective observational study of all patients who received ICIs from a single cancer center between 2011 and 2018. Patients were followed for 12 months after initiation of ICIs or until death. Common Terminology for Cancer Adverse Events version 5.0 criteria were used to grade the severity of hyponatremia and other electrolyte abnormalities. The predictors of severe (Grade 3 or 4) hyponatremia were determined using a multivariable logistic regression model. The etiology of Grade 3 or 4 hyponatremia was determined by chart review.ResultsA total of 2458 patients were included. Their average age was 64 years [standard deviation (SD) 13], 58% were male and 90% were white. In the first year after starting ICIs, 62% experienced hyponatremia (sodium <134 mEq/L) and 136 (6%) experienced severe hyponatremia (<124 mEq/L). Severe hyponatremia occurred on average 164 days (SD 100) after drug initiation. Only nine cases of severe hyponatremia were due to endocrinopathies (0.3% overall incidence). Risk factors for severe hyponatremia included ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor) use, diuretic use and non-White race. Other severe electrolyte abnormalities were also commonly observed: severe hypokalemia (potassium <3.0 mEq/L) occurred in 6%, severe hyperkalemia (potassium ≥6.1 mEq/L) occurred in 0.6%, severe hypophosphatemia (phosphorus <2 mg/dL) occurred in 17% and severe hypocalcemia (corrected calcium <7.0 mg/dL) occurred in 0.2%.ConclusionsHyponatremia is common in cancer patients receiving ICIs. However, endocrinopathies are an uncommon cause of severe hyponatremia.

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Catenin Alpha-2 Mutation Changes the Immune Microenvironment in Lung Adenocarcinoma Patients Receiving Immune Checkpoint Inhibitors.

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