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• W3036095571 abstract "Dear Editor, Immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), or programmed cell death protein 1 (PD-1) and its ligand (PD-L1) interaction achieve a significant improvement in overall survival (OS) and revolutionize treatment paradigms in many types of cancers.1, 2 Despite of the durable antitumor effect, ICIs could only benefit a minority of patients (∼20%) without effective predictive biomarkers.3 Therefore, there is an urgent need to develop novel biomarkers for the majority of patients, who do not respond to ICIs monotherapy. Telomerase reverse transcriptase (TERT), as the catalytic subunit of telomerase, plays a critical role in modulating telomerase activity and immortalization of cancer cells.4-7 It plays a crucial role in the tumorigenesis, cancer cell proliferation, invasion, and DNA damage response.4, 7 Recently, an elegant study found that short telomere length could cause a primary T cell immunodeficiency,8 suggesting the contribution of telomere length to T cell apoptosis and function. Therefore, it is valuable to investigate the predictive value of TERT alterations for ICIs treatment outcome in multiple cancers. We identified a cohort of 43 910 cancer patients with 46 237 sequenced tumor samples, together with sequenced data and collected clinical information from the cBioPortal online database (https://www.cbioportal.org) (Figure S1). The prevalence of TERT alterations was 6.7%, with patients with thyroid cancer having the highest levels of TERT alterations (60.2%, 139/231; Figure S2). Most of the alterations were somatic mutations (73.1%, 2258/3091), especially promoter mutations (75.0%, 1693/2258). We then investigated the prevalence and spectrum of TERT alterations in early-stage (TCGA cohort, N = 10 967) and advanced-stage cancers (MSK-IMPACT cohort, N = 10 945). The results showed that advanced-stage cancers (15.2%, 1659/10 945) had significantly higher frequency of TERT alterations than early-stage cancers (5.5%, 604/10 967; P < .0001). Most detected TERT alterations were amplifications in early-stage cohort (Figure S3A), whereas most were TERT somatic mutations including promoter mutations in advanced-stage cancers (Figure S3B). In MSK-IMPACT cohort,9 we found that TMB of patients with TERT alterations was significantly higher than those without these alterations (17 vs 6 mut/Mb, P < .0001; Figure S4A). This was validated in the ICI-treated cohort that included 1661 patients (TMB of TERT alterations vs wild type: 20 vs 9 mut/Mb, P < .0001; Figure S4B). Notably, cancers with multiple TERT alterations had the highest TMB level in both cohorts (Figures S4C and S4D). Next, we evaluated the association between TERT alterations and clinical outcome. We first found that patients with TERT alterations showed a significantly shorter OS (38 vs 113 months; HR = 1.90; 95% CI, 1.73-2.09; P < .0001; Figure 1A) than those without in whole group. In the ICI treatment cohort,10 we first identified 1661 patients with different cancers receiving ICI therapy and 521 of them with TERT alterations. Although clinicopathological features, including age, sex, sample type, and tumor purity, were not well balanced (Table S1), patients with TERT alterations had a substantially prolonged OS of 24 versus 17 months in the wild-type group (HR = 0.78; 95% CI, 0.68-0.91; P = .0016; Figure 1B). Although TERT alterations were associated with higher level of TMB, multivariate analysis revealed that TERT alterations were associated with markedly longer OS than wild type independent of TMB (HR = 0.77; 95% CI, 0.67-0.91; P = .0020; Table S2). Notably, we also observed the association between TERT alterations and prolonged OS in patients with microsatellite-stable solid tumors (not reached vs 20 months; HR = 0.35; 95% CI, 0.14-0.88; P = .0248; Figure S5). Subgroup analysis revealed that patients with TERT promoter mutations also had the better OS than those with TERT wild type (22 vs 17 months, P = .0225; Figure 1C). Interestingly, in nonsmall-cell lung cancer (NSCLC) treated with ICI, patients with TERT promoter mutations had the longest progression-free survival (PFS) than other alterations and wild-type groups (7.9 vs 2.6 vs 3.2 months; P = .0765; Figure 1D). To validate the abovementioned predictive value of TERT subtypes in NSCLC, we independently identified 158 patients with advanced NSCLC who received ICI monotherapy from three medical centers. Clinicopathological parameters were well balanced between TERT alterations and wild-type groups (Figure 1E). Similarly, we found that patients with TERT-altered NSCLC had significantly better objective response rate (35.7% vs 17.4%; P = .044) and prolonged PFS than wild type (8.8 vs 3.1 months; P = .0248; Figure 1F). Moreover, patients with TERT promoter mutations had the longest PFS than other alterations and wild-type groups (9.7 vs 6.3 vs 3.1 months; P = .0333; Figure 1G). Association between TERT alterations and clinical outcome. A, Prognostic value of TERT alterations in all cancers. B, Predictive value of TERT alterations in patients who received ICI therapy. C, Subgroup analysis of the predictive value of TERT alterations subtypes in patients who received ICI treatment. D, Subgroup analysis of the predictive value of TERT alterations subtypes in nonsmall-cell lung cancer patients who received ICI treatment. E, Baseline features of NSCLC patients with TERT alterations versus wild type from real-world cohort. F, Predictive value of TERT alterations in patients with advanced NSCLC who received ICI monotherapy in real-world cohort. G, Subgroup analysis of the predictive value of TERT alterations subtypes in patients with advanced NSCLC who received ICI monotherapy in real-world cohort Abbreviations: CR, complete response; Mut, somatic mutations; PD, disease progression; PR, partial response; SD, stable disease; WT, wild type. To depict the tumor immune microenvironment of TERT-altered tumors, we surveyed the relationship between TERT alterations and eight common immune infiltrates including total CD3+ T cells, CD8+ T cells, cytotoxic lymphocytes, B lineage, NK cells, monocytic lineage, neutrophils, and myeloid dendritic cells across different cancer types (Figure 2). The results showed that tumor-infiltrating CD8+ T cells, especially cytotoxic lymphocytes, were generally more abundant in the TERT-altered tumors compared with those in the wild-type tumors across multiple cancer types (Figure 2A-D), whereas neutrophils were lower in TERT-altered tumors than in wild type (Figures 2A and 2I). The results of signaling pathways in HALLMARK gene set collection showed that several signatures associated with antitumor immunity including DNA repair, unfolded protein response, E2F targets, cholesterol homeostasis, and so on were significantly higher in TERT-altered tumors, whereas hallmarks associated with immune inhibitory function including hedgehog pathway, NOTCH signaling, transforming growth factor-β (TGF-β) signaling, angiogenesis, hypoxia, and so on were obviously higher in TERT wild-type tumors (Figure 2J). Immune landscape analysis of TERT-altered and wild-type tumors. A, Heatmap depicting the log2-transformed fold change in the mean tumor-infiltrating leukocytes MCP-counter scores of the TERT-altered tumors compared to TERT wild-type tumors across different cancer types. B, Comparison of T cell abundance between the TERT-altered and TERT wild-type tumors. C, Comparison of CD8+ T cell abundance between the TERT-altered and TERT wild-type tumors. D, Comparison of cytotoxic lymphocyte abundance between the TERT-altered and TERT wild-type tumors. E, Comparison of NK cell abundance between the TERT-altered and TERT wild-type tumors. F, Comparison of B lineage abundance between the TERT-altered and TERT wild-type tumors. G, Comparison of monocytic lineage abundance between the TERT-altered and TERT wild-type tumors. H, Comparison of myeloid dendritic cell abundance between the TERT-altered and TERT wild-type tumors. I, Comparison of neutrophil abundance between the TERT-altered and TERT wild-type tumors. J, Heatmap depicting the mean differences in immune-related hallmarks between the TERT-altered and TERT wild-type tumors across different cancer types Abbreviations: CESC, cervical squamous-cell carcinoma and endocervical adenocarcinoma; CRC, colorectal cancer; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous-cell carcinoma; MCP, microenvironment cell populations; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; UCEC, uterine corpus endometrial carcinoma. In summary, the current study first provides the evidence that TERT alterations were associated with enhanced tumor immunogenicity and inflamed antitumor immunity, which result in prolonged OS in cancer patients treated with ICIs. The predictive value of TERT alterations was independent of tumor mutational burden and microsatellite status, suggesting that TERT alterations could be considered as a potential pan-cancer predictive biomarker for ICI treatment. For the future, we still need to investigate the exact molecular mechanism, and large-scale, prospective studies are also warranted. This study was supported in part by grants from the National Natural Science Foundation of China (No. 81871865 and 81972167), the Backbone Program of Shanghai Pulmonary Hospital (No. FKGG1802), and the Shanghai Municipal Science and Technology Commission Medical Guidance Project (No. 17411969200). The authors declare no conflict of interest. Tao Jiang and Caicun Zhou designed this study. Tao Jiang, Qingzhu Jia, Wenfeng Fang, Shengxiang Ren, Xiaoxia Chen, and Chunxia Su collected the clinical and sequenced data. Tao Jiang, Qingzhu Jia, and Shengxiang Ren performed the statistical analyses. Tao Jiang, Shengxaing Ren, Li Zhang, and Caicun Zhou drafted the manuscript. Li Zhang and Caicun Zhou provided critical comments and suggestions and revised the manuscript. All authors read and approved the final version of the manuscript. All the data and materials are available. All the authors consent for publication. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W3036095571 title "Pan‐cancer analysis identifies <i>TERT</i> alterations as predictive biomarkers for immune checkpoint inhibitors treatment" @default.
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