ATM Mutations Benefit Bladder Cancer Patients Treated With Immune Checkpoint Inhibitors by Acting on the Tumor Immune Microenvironment

Yi, Ruibin; Lin, Anqi; Cao, Manming; Xu, Aiming; Luo, Peng; Zhang, Jian

doi:10.3389/fgene.2020.00933

Cited by 35 publications

(30 citation statements)

References 58 publications

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“…An increasing number of studies showed that driver gene mutations may cause differences in the efficacy of ICIs by affecting the tumor immune microenvironment ( Huang et al, 2020 ; Lin A. et al, 2020 ; Lin W. et al, 2020 ; Niu et al, 2020 ; Yi et al, 2020 ; Zhang et al, 2020 ). Dong et al (2017a) indicated that non-small cell lung cancer patients with EGFR mutations responded poorly to PD-(L)1 inhibitors, which may be related to reduced CD8 + T lymphocyte infiltration and low immunogenicity.…”

Section: Introductionmentioning

confidence: 99%

Age and Mutations as Predictors of the Response to Immunotherapy in Head and Neck Squamous Cell Cancer

Zhang

Lin

et al. 2020

Front. Cell Dev. Biol.

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The immunosuppressive tumor microenvironment plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSC). Compared to traditional chemoradiotherapy, immune checkpoint inhibitors (ICIs) have become increasingly important in HNSC therapy. Prior studies linked the efficacy of ICIs to PD-L1, microsatellite instability (MSI), HPV infection, tumor mutation burden (TMB), and tumor lymphocyte infiltration in patients with HNSC, but further verification is needed. Additional predictors are needed to recognize HNSC patients with a good response to ICIs. We collected the clinical information and mutation data of HNSC patients from Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA) databases to generate two clinical cohorts. The MSKCC cohort was used to recognize predictors related to the efficacy of ICIs, and the TCGA cohort was used to further examine the immune microenvironment features and signaling pathways that are significantly enriched in the subgroups of predictors. Multivariate Cox regression analysis indicated that age (HR = 0.50, p = 0.014) and ARID1A (HR = 0.13, p = 0.048), PIK3CA (HR = 0.45, p = 0.021), and TP53 (HR = 1.82, p = 0.035) mutations were potential predictors for ICI efficacy in HNSC patients. Age > 65 years and ARID1A or PIK3CA mutations correlated with good overall survival (OS). TP53 mutant-type (MT) patients experienced a worse prognosis than TP53 wild-type (WT) patients. The subgroups associated with a good prognosis (age > 65 years, ARID1A-MT, and PIK3CA-MT) universally had a high TMB and increased expression of immune checkpoint molecules. Although TP53-MT was associated with a high TMB, the expression of most immune checkpoint molecules and immune-related genes was lower in TP53-MT patients than TP53-WT patients, which may reflect low immunogenicity. Pathways related to the immunosuppressive tumor microenvironment were mostly enriched in the subgroups associated with a poor prognosis (age ≤ 65 years, low TMB, ARID1A-WT, PIK3CA-WT, and TP53-MT). In conclusion, the factors age > 65 years, PIK3CA-MT, and ARID1A-MT predicted favorable efficacy for ICI treatment in HNSC patients, and TP53 mutation was a negative predictor.

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Section: Introductionmentioning

confidence: 99%

Age and Mutations as Predictors of the Response to Immunotherapy in Head and Neck Squamous Cell Cancer

Zhang

Lin

et al. 2020

Front. Cell Dev. Biol.

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“…To determine how the ICI score enhanced the immunogenicity of bladder cancer and activated antitumor immunity, we compared the expression of 74 immune-related genes between the high ICI score and low ICI score groups. The 74 immune-related genes were obtained from a published article ( Yi et al, 2020 ). The results revealed that the expression of 53 immune-related genes was significantly different between the high and low ICI score group ( Supplementary Figure 7 ).…”

Section: Resultsmentioning

confidence: 99%

Identification of Immune-Related Subtypes and Characterization of Tumor Microenvironment Infiltration in Bladder Cancer

Huang

Liu

Zhu

et al. 2021

Front. Cell Dev. Biol.

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Tumors are closely related to the tumor microenvironment (TME). The complex interaction between tumor cells and the TME plays an indisputable role in tumor development. Tumor cells can affect the TME, promote tumor angiogenesis and induce immune tolerance by releasing cell signaling molecules. Immune cell infiltration (ICI) in the TME can affect the prognosis of patients with bladder cancer. However, the pattern of ICI of the TME in bladder cancer has not yet been elucidated. Herein, we identified three distinct ICI subtypes based on the TME immune infiltration pattern of 584 bladder cancer patients using the ESTIMATE and CIBERSORT algorithms. Then, we identified three gene clusters based on the differentially expressed genes (DEGs) between the three ICI subtypes. In addition, the ICI score was determined using single sample gene set enrichment analysis (ssGSEA). The results suggested that patients in the high ICI score subgroup had a favorable prognosis and higher expression of checkpoint-related and immune activity-related genes. The high ICI score subgroup was also linked to increased tumor mutation burden (TMB) and neoantigen burden. A cohort treated with anti-PD-L1 immunotherapy confirmed the therapeutic advantage and clinical benefit of patients with higher ICI scores. In the end, our study also shows that the ICI score represents an effective prognostic predictor for evaluating the response to immunotherapy. In conclusion, our study deepened the understanding of the TME, and it provides new ideas for improving patients’ response to immunotherapy and promoting individualized tumor immunotherapy in the future.

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“… 38 Recently, it has been shown that bladder cancer patients with mutated ATM had better benefits from immune checkpoint inhibitor (ICI) therapy. 39 Inactivation of FBXW7 causes genomic instability. 40 Importantly, mutations in ATM and FBXW7 genes correlate with higher TMB levels in several cancer types, including OC.…”

Section: Discussionmentioning

confidence: 99%

The mutational load and a T-cell inflamed tumour phenotype identify ovarian cancer patients rendering tumour-reactive T cells from PD-1+ tumour-infiltrating lymphocytes

et al. 2021

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Background Adoptive immunotherapy with tumour-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as PD-1, for tumour-specific T-cell enrichment, and the identification of predictive factors that help identify those patients capable of rendering tumour-reactive TILs. We have investigated this in ovarian cancer (OC) patients as candidates for TIL therapy implementation. Methods PD-1− and PD-1+ CD8 TILs were isolated from ovarian tumours and expanded cells were tested against autologous tumour cells. Baseline tumour samples were examined using flow cytometry, multiplexed immunofluorescence and Nanostring technology, for gene expression analyses, as well as a next-generation sequencing gene panel, for tumour mutational burden (TMB) calculation. Results Tumour-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Importantly, a high TIL density in the fresh tumour, the presence of CD137+ cells within the PD-1+CD8+ TIL subset and their location in the tumour epithelium, together with a baseline T-cell-inflamed genetic signature and/or a high TMB, are features that identify patients rendering tumour-reactive TIL products. Conclusion We have demonstrated that PD-1 identifies ovarian tumour-specific CD8 TILs and has uncovered predictive factors that identify OC patients who are likely to render tumour-specific cells from PD-1+ TILs.

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ATM Mutations Benefit Bladder Cancer Patients Treated With Immune Checkpoint Inhibitors by Acting on the Tumor Immune Microenvironment

Cited by 35 publications

References 58 publications

Age and Mutations as Predictors of the Response to Immunotherapy in Head and Neck Squamous Cell Cancer

Age and Mutations as Predictors of the Response to Immunotherapy in Head and Neck Squamous Cell Cancer

Identification of Immune-Related Subtypes and Characterization of Tumor Microenvironment Infiltration in Bladder Cancer

The mutational load and a T-cell inflamed tumour phenotype identify ovarian cancer patients rendering tumour-reactive T cells from PD-1+ tumour-infiltrating lymphocytes

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