Association of <i>PTPRT</i> mutations with immune checkpoint inhibitors response and outcome in melanoma and non‐small cell lung cancer

Zhang, Wenjing; Shi, Fuyan; Li, Yuting; Sheng, Chao; Wang, Shuzhen; Wang, Qinghua

doi:10.1002/cam4.4472

Cited by 24 publications

(29 citation statements)

References 71 publications

(133 reference statements)

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“…Of them, AR has been demonstrated to negatively regulate PD-L1 expression, and therefore lower AR-expressed tumors achieved a better response to immunotherapy in hepatocellular carcinoma ( Jiang et al, 2020 ). In addition, patients with PTPRT mutations harbored favorable ORR and survival outcomes in several tumor types ( Zhang et al, 2022 ). However, the associations of other genes used in our model with ICI efficacy have not been reported, although some of them have been found to play critical roles in cancer, such as COL5A2 ( Han et al, 2022 ), FAT2 ( Gao et al, 2014 ), ITPR3 ( Wu et al, 2021 ), PCDH20 ( Wang et al, 2016 ), and UTRN ( Zhou et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors

Cao

et al. 2022

Front. Cell Dev. Biol.

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Background: The immunotherapy efficacy in gastric cancer (GC) is limited. Cancer-associated fibroblasts (CAFs) induce primary resistance to immunotherapy. However, CAF infiltration in tumors is difficult to evaluate due to the lack of validated and standardized quantified methods. This study aimed to investigate the impact of infiltrating CAFs alternatively using fibroblast-associated mutation scoring (FAMscore).Methods: In a GC cohort from Affiliated Hospital of Jiangsu University (AHJU), whole exon sequencing of genomic mutations, whole transcriptome sequencing of mRNA expression profiles, and immunofluorescence staining of tumor-infiltrating immune cells were performed. GC data from The Cancer Genome Atlas were used to identify genetic mutations which were associated with overall survival (OS) and impacted infiltrating CAF abundance determined by transcriptome-based estimation. FAMscore was then constructed through a least absolute shrinkage and selection operator Cox regression model and further validated in AHJU. The predictive role of FAMscore for immunotherapy outcomes was tested in 1 GC, one melanoma, and two non-small-cell lung cancer (NSCLC-1 and -2) cohorts wherein participants were treated by immune checkpoint inhibitors.Results: FAMscore was calculated based on a mutation signature consisting of 16 genes. In both TCGA and AHJU, a high FAMscore was an independent predictor for poor OS of GC patients. FAMscore was associated with immune-associated genome biomarkers, immune cell infiltration, and signaling pathways of abnormal immunity. Importantly, patients with high FAMscore presented inferiority in the objective response rate of immunotherapy compared to those with low FAMscore, with 14.6% vs. 66.7% (p<0.001) in GC, 19.6% vs. 68.2% (p<0.001) in NSCLC-1, 23.1% vs 75% (p = 0.007) in NSCLC-2, and 40.9% vs 75% (p = 0.037) in melanoma. For available survival data, a high FAMscore was also an independent predictor of poor progression-free survival in NSCLC-1 (HR = 2.55, 95% CI: 1.16–5.62, p = 0.02) and NSCLC-2 (HR = 5.0, 95% CI: 1.13–22.19, p = 0.034) and poor OS in melanoma (HR = 3.48, 95% CI: 1.27–9.55, p = 0.015).Conclusions: Alternative evaluation of CAF infiltration in GC by determining the FAMscore could independently predict prognosis and immunotherapy outcomes. The FAMscore may be used to optimize patient selection for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors

Cao

et al. 2022

Front. Cell Dev. Biol.

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“…Several studies suggested that PTPRT mutation is positively correlated with TMB, and patients with PTPRT mutation might benefit from ICI therapy, indicating that PTPRT is a potential biomarker in immunotherapy [ 8 , 9 ]. Based on the prediction based on recurrent mutations in PTPRT , we identified potential PTPRT neoantigens ( Table 2 ) that might have a therapeutic value in immunotherapies, for example, cancer vaccines or T cell therapies.…”

Section: Discussionmentioning

confidence: 99%

“…The gene may be involved in both signal transduction and cellular adhesion and is also known to inhibit malignant cell proliferation by inhibiting the STAT3 pathway [ 4 – 7 ]. Recent studies have reported that PTPRT mutations may be associated with the tumor mutation burden (TMB) and could provide clinically predictive implications for immune checkpoint inhibitor (ICI) therapies [ 8 , 9 ]. Hu et al reported that PTPRT may be involved in the early metastatic seeding of colorectal cancer [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Association of PTPRT Mutations with Cancer Metastasis in Multiple Cancer Types

Chen

Liu

et al. 2022

BioMed Research International

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Metastasis is one of the characteristics of advanced cancer and the primary cause of cancer-related deaths from cancer, but the mechanism underlying metastasis is unclear, and there is a lack of metastasis markers. PTPRT is a protein-coding gene involved in both signal transduction and cellular adhesion. It is also known as a tumor suppressor gene that inhibits cell malignant proliferation by inhibiting the STAT3 pathway. Recent studies have reported that PTPRT is involved in the early metastatic seeding of colorectal cancer; however, the correlation between PTPRT and metastasis in other types of cancer has not been revealed. A combined analysis using a dataset from the genomics evidence neoplasia information exchange (GENIE) and cBioPortal revealed that PTPRT mutation is associated with poor prognosis in pan-cancer and non-small-cell lung cancer. The mutations of PTPRT or “gene modules” containing PTPRT are significantly enriched in patients with metastatic cancer in multiple cancers, suggesting that the PTPRT mutations serve as potential biomarkers of cancer metastasis.

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“…Multiple studies have revealed the potential implications of TMB for evaluating cancer immunotherapeutic efficacy [ 8 , 12 , 13 , 53 ]. However, in clinical practice, the determination of TMB needs to conduct whole-exome mutational detection [ 54 ]. Another disadvantage of the TMB application is the uncertain cut-off values in distinct cancer types [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer

Zhang

Lin

Shi

et al. 2022

Cancers

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Immune checkpoint inhibitors (ICIs) markedly promote the survival outcome of advanced melanoma and non-small cell lung cancer (NSCLC). Clinically, favorable ICI treatment efficacy is noticed only in a smaller proportion of patients. Heparan sulfate proteoglycan 2 (HSPG2) frequently mutates in both tumors. Herein, we aim to investigate the immunotherapeutic and immunological roles of HSPG2 mutations in melanoma and NSCLC. A total of 631 melanoma samples and 109 NSCLC samples with both somatic mutational profiles and clinical immunotherapy data were curated. In addition, by using The Cancer Genome Atlas data, genomic and immunological traits behind HSPG2 mutations were elucidated. Melanoma patients with HSPG2 mutations had a markedly extended ICI outcome than other patients. An association between HSPG2 mutations and the improved outcome was further confirmed in NSCLC. In addition, an elevated ICI response rate was presented in HSPG2-mutated NSCLC patients (81.8% vs. 29.7%, p = 0.002). Subsequent analyses revealed that HSPG2-mutated patients had a favorable abundance of response immunocytes, an inferior abundance of suppression immunocytes, enhanced mutational burden, and interferon response-relevant signaling pathways. We uncovered that HSPG2 mutations were predictive of a better ICI response and associated with preferable immunogenicity, which may be considered as a genomic determinant to customize biotherapy strategies.

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Association of PTPRT mutations with immune checkpoint inhibitors response and outcome in melanoma and non‐small cell lung cancer

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 24 publications

References 71 publications

A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors

A Genomic Signature Reflecting Fibroblast Infiltration Into Gastric Cancer Is Associated With Prognosis and Treatment Outcomes of Immune Checkpoint Inhibitors

Association of PTPRT Mutations with Cancer Metastasis in Multiple Cancer Types

HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer

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