Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma

Ma, Yuxiang; Chen, Xi; Wang, Ao; Zhao, Hongyun; Q, Lin; Bao, Hua; Zhang, Yang; Hong, Shaodong; Tang, Wanxiangfu; Huang, Yan; Yang, Yunpeng; Wu, Xue; Shao, Yang; Fang, Wenfeng; Zhang, Li

doi:10.1136/jitc-2020-002014

Cited by 17 publications

(18 citation statements)

References 41 publications

(37 reference statements)

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“…In NPC clinical trials, the copy number gain of the cytotoxic effectors, GZMB and GZMH, was associated with increased survival during anti-PD1 treatment. 57 Thus, in rNPC samples, with elevated cytotoxic and exhausted features, there were sufficient evidence to conjecture rNPC respond better in ICI than primary tumor.…”

Section: Discussionmentioning

confidence: 98%

Dissecting the heterogeneity of the microenvironment in primary and recurrent nasopharyngeal carcinomas using single-cell RNA sequencing

et al. 2022

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Nasopharyngeal carcinoma (NPC) has a 10–15% recurrence rate, while no long term or durable treatment options are currently available. Single-cell profiling in recurrent NPC (rNPC) may aid in designing effective anticancer therapies, including immunotherapies. For the first time, we profiled the transcriptomes of ∼60,000 cells from four primary NPC and two rNPC cases to provide deeper insights into the dynamic changes in rNPC within radiation fields. Heterogeneity of both immune cells (T, natural killer, B, and myeloid cells) and tumor cells was characterized. Recurrent samples showed increased infiltration of regulatory T cells in a highly immunosuppressive state and CD8 + T cells in a highly cytotoxic and dysfunctional state. Enrichment of M2-polarized macrophages and LAMP3 + dendritic cells conferred enhanced immune suppression to rNPC. Furthermore, malignant cells showed enhanced immune-related features, such as antigen presentation. Elevated regulatory T cell levels were associated with a worse prognosis, with certain receptor-ligand communication pairs identified in rNPC. Even with relatively limited samples, our study provides important clues to complement the exploitation of rNPC immune environment and will help advance targeted immunotherapy of rNPC.

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Section: Discussionmentioning

confidence: 98%

Dissecting the heterogeneity of the microenvironment in primary and recurrent nasopharyngeal carcinomas using single-cell RNA sequencing

et al. 2022

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“…Granzyme B is a serine protease released by CD8 + T cells and natural killer cells and functions as a downstream effector of tumor cytotoxic T cells 17,18 . A recent study found that alterations in the Granzyme B gene (GZMB/H) negatively predicted ICB e cacy in nasopharyngeal cancer patients 19 . Thus, the role of Granzyme B protein as a biomarker was investigated in our study.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal High-Dimensional Analysis Identifies Biomarkers of Response to Anti-PD-1 Immunotherapy

Fan

Jiang

et al. 2021

SSRN Journal

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The response to immunotherapy could be better predicted by using a wide set of biomarkers, including serum tumor markers; however, robust immune markers associated with e cacy have yet to be validated.In this study, changes in immune cell subsets from NSCLC patients treated with anti-PD1 therapy were longitudinally monitored by high-dimensional cytometry by time of ight (CyTOF) and Meso Scale Discovery (MSD) multi-cytokines kits. The frequencies of circulating CD8 + and CD8 + CD101 hi TIM3 + (CCT T) subsets were signi cantly correlated with clinical response and survival. Enrichment of these populations in peripheral blood mononuclear cells (PBMCs) indicated a poor clinical response to ICB therapy. Cell function assays revealed that these subsets were remarkably impaired, which supported the poor outcomes observed. Additionally, longitudinal analysis showed that KLRG1 expression and cytokines were associated with the response to therapy. Overall, our results provide novel potential biomarkers for guiding the management of NSCLC patients eligible to anti-PD-1 therapy, and contribute insights for new therapeutic strategies.

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“…Intriguingly, the expression of HLAB gene, which was also part of the HLA complex, was reportedly associated with tumor progression in CRC [31]. Furthermore, ARHGEF1, CFAP65, PDGFRB and CLEC5A were labeled as prognostic marker by the Human Protein Atlas in renal and breast cancer, endometrial cancer, renal and urothelial cancer, and ovarian cancer, respectively [32,33]. The predictive model established through LASSO and LOOCV was based on 23 DMRs, most of them were located in the gene coding or promoter regions.…”

Section: Discussionmentioning

confidence: 99%

Identification of DNA methylation biomarkers for risk of liver metastasis in early-stage colorectal cancer

Guo

Tang³

et al. 2021

Clin Epigenet

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Background Liver metastases can occur even in CRC patients who underwent curative surgery. While evidence suggested that adjuvant chemotherapy can help to reduce the occurrence of liver metastases for certain patients, it is not a recommended routine as the side effects outweigh the potential benefits, especially in Stage II CRC patients. This study aims to construct a model for predicting liver metastasis risk using differential methylation signals in primary CRC tumors, which can facilitate the decision for adjuvant chemotherapy. Methods Fifty-nine stage I/II and IV CRC patients were enrolled. Primary tumor, adjacent normal tissue, and metastatic tumor tissues were subject to targeted bisulfite sequencing for DNA methylation. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was used to identify potential DMRs for predicting liver metastasis of CRC. Results We identified a total of 241,573 DMRs by comparing the DNA methylation profile of primary tumors of stage II patients who developed metastasis to those who were metastasis-free during the follow up period. 213 DMRs were associated with poor prognosis, among which 182 DMRS were found to be hypermethylated in the primary tumor of patients with metastases. Furthermore, by using the LASSO regression model, we identified 23 DMRs that contributed to a high probability of liver metastasis of CRC. The leave-one-out cross validation (LOOCV) was used to evaluate model predictive performance at an AUC of 0.701. In particular, 7 out of those 23 DMRs were found to be in the promoter region of genes that were previously reported prognostic biomarkers in diverse tumor types, including TNNI2, PAX8, GUF1, KLF4, EVI2B, CEP112, and long non-coding RNA AC011298. In addition, the model was also able to distinguish metastases of different sites (liver or lung) at an AUC of 0.933. Conclusion We have identified DNA methylation biomarkers associated with the risk of cancer liver metastasis in early-stage CRC patients. A risk prediction model based on those epigenetic markers was proposed for outcome assessment.

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Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma

Cited by 17 publications

References 41 publications

Dissecting the heterogeneity of the microenvironment in primary and recurrent nasopharyngeal carcinomas using single-cell RNA sequencing

Dissecting the heterogeneity of the microenvironment in primary and recurrent nasopharyngeal carcinomas using single-cell RNA sequencing

Longitudinal High-Dimensional Analysis Identifies Biomarkers of Response to Anti-PD-1 Immunotherapy

Identification of DNA methylation biomarkers for risk of liver metastasis in early-stage colorectal cancer

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