Non‑small cell lung cancer carrying PBRM1 mutation suggests an immunologically cold phenotype leading to immunotherapy failure even with high TMB
Abstract High tumor mutation load (TMB-H, or TMB ≥ 10) has been approved by the U.S. FDA as a biomarker for pembrolizumab treatment of solid tumors, including non‑small cell lung cancer (NSCLC). Patients with cancer who have immunotherapy-resistant gene mutations cannot achieve clinical benefits eve...
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| Format: | Article |
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Nature Portfolio
2022-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-25050-3 |
| _version_ | 1811190490559676416 |
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| author | Xia-ye Miao Hao Wu Bi-cheng Ye Qian-wen Yi Fang-nan Lin Yi-lin Wang Chuan-li Ren Yan-fang Jiang Ang Li |
| author_facet | Xia-ye Miao Hao Wu Bi-cheng Ye Qian-wen Yi Fang-nan Lin Yi-lin Wang Chuan-li Ren Yan-fang Jiang Ang Li |
| author_sort | Xia-ye Miao |
| collection | DOAJ |
| description | Abstract High tumor mutation load (TMB-H, or TMB ≥ 10) has been approved by the U.S. FDA as a biomarker for pembrolizumab treatment of solid tumors, including non‑small cell lung cancer (NSCLC). Patients with cancer who have immunotherapy-resistant gene mutations cannot achieve clinical benefits even in TMB-H. In this study, we aimed to identify gene mutations associated with immunotherapy resistance and further informed mechanisms in NSCLC. A combined cohort of 350 immune checkpoint blockade-treated patients from Memorial Sloan Kettering Cancer Center (MSKCC) was used to identify genes whose mutations could negatively influence immunotherapy efficacy. An external NSCLC cohort for which profession-free survival (PFS) data were available was used for independent validation. CIBERSORT algorithms were used to characterize tumor immune infiltrating patterns. Immunogenomic features were analysed in the TCGA NSCLC cohort. We observed that PBRM1 mutations independently and negatively influence immunotherapy efficacy. Survival analysis showed that the overall survival (OS) and PFS of patients with PBRM1 mutations (MT) were significantly shorter than the wild type (WT). Moreover, compared with PBRM1-WT/TMB-H group, OS was worse in the PBRM1-MT/TMB-H group. Notably, in patients with TMB-H/PBRM1-MT, it was equal to that in the low-TMB group. The CIBERSORT algorithm further confirmed that the immune infiltration abundance of CD8+ T cells and activated CD4+ memory T was significantly lower in the MT group. Immunogenomic differences were observed in terms of immune signatures, T-cell receptor repertoire, and immune-related genes between WT and MT groups. Nevertheless, we noticed an inverse relationship, given that MT tumors had a higher TMB than the WT group in MSKCC and TCGA cohort. In conclusion, our study revealed that NSCLC with PBRM1 mutation might be an immunologically cold phenotype and exhibited immunotherapy resistance. NSCLC with PBRM1 mutation might be misclassified as immunoresponsive based on TMB. |
| first_indexed | 2024-04-11T14:52:05Z |
| format | Article |
| id | doaj.art-c1fc5f1cacc14c2fbc2f3564c779d8be |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T14:52:05Z |
| publishDate | 2022-12-01 |
| publisher | Nature Portfolio |
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| spelling | doaj.art-c1fc5f1cacc14c2fbc2f3564c779d8be2022-12-22T04:17:26ZengNature PortfolioScientific Reports2045-23222022-12-011211810.1038/s41598-022-25050-3Non‑small cell lung cancer carrying PBRM1 mutation suggests an immunologically cold phenotype leading to immunotherapy failure even with high TMBXia-ye Miao0Hao Wu1Bi-cheng Ye2Qian-wen Yi3Fang-nan Lin4Yi-lin Wang5Chuan-li Ren6Yan-fang Jiang7Ang Li8Department of Laboratory Medicine, Clinical College of Yangzhou UniversityDepartment of Oncology, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’anSchool of Clinical Medicine, Yangzhou Polytechnic CollegeDepartment of Pediatrics, The First Affiliated Hospital of Bengbu Medical CollegeKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin UniversityKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin UniversityDepartment of Laboratory Medicine, Clinical College of Yangzhou UniversityKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin UniversityKey Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, The First Hospital of Jilin UniversityAbstract High tumor mutation load (TMB-H, or TMB ≥ 10) has been approved by the U.S. FDA as a biomarker for pembrolizumab treatment of solid tumors, including non‑small cell lung cancer (NSCLC). Patients with cancer who have immunotherapy-resistant gene mutations cannot achieve clinical benefits even in TMB-H. In this study, we aimed to identify gene mutations associated with immunotherapy resistance and further informed mechanisms in NSCLC. A combined cohort of 350 immune checkpoint blockade-treated patients from Memorial Sloan Kettering Cancer Center (MSKCC) was used to identify genes whose mutations could negatively influence immunotherapy efficacy. An external NSCLC cohort for which profession-free survival (PFS) data were available was used for independent validation. CIBERSORT algorithms were used to characterize tumor immune infiltrating patterns. Immunogenomic features were analysed in the TCGA NSCLC cohort. We observed that PBRM1 mutations independently and negatively influence immunotherapy efficacy. Survival analysis showed that the overall survival (OS) and PFS of patients with PBRM1 mutations (MT) were significantly shorter than the wild type (WT). Moreover, compared with PBRM1-WT/TMB-H group, OS was worse in the PBRM1-MT/TMB-H group. Notably, in patients with TMB-H/PBRM1-MT, it was equal to that in the low-TMB group. The CIBERSORT algorithm further confirmed that the immune infiltration abundance of CD8+ T cells and activated CD4+ memory T was significantly lower in the MT group. Immunogenomic differences were observed in terms of immune signatures, T-cell receptor repertoire, and immune-related genes between WT and MT groups. Nevertheless, we noticed an inverse relationship, given that MT tumors had a higher TMB than the WT group in MSKCC and TCGA cohort. In conclusion, our study revealed that NSCLC with PBRM1 mutation might be an immunologically cold phenotype and exhibited immunotherapy resistance. NSCLC with PBRM1 mutation might be misclassified as immunoresponsive based on TMB.https://doi.org/10.1038/s41598-022-25050-3 |
| spellingShingle | Xia-ye Miao Hao Wu Bi-cheng Ye Qian-wen Yi Fang-nan Lin Yi-lin Wang Chuan-li Ren Yan-fang Jiang Ang Li Non‑small cell lung cancer carrying PBRM1 mutation suggests an immunologically cold phenotype leading to immunotherapy failure even with high TMB Scientific Reports |
| title | Non‑small cell lung cancer carrying PBRM1 mutation suggests an immunologically cold phenotype leading to immunotherapy failure even with high TMB |
| title_full | Non‑small cell lung cancer carrying PBRM1 mutation suggests an immunologically cold phenotype leading to immunotherapy failure even with high TMB |
| title_fullStr | Non‑small cell lung cancer carrying PBRM1 mutation suggests an immunologically cold phenotype leading to immunotherapy failure even with high TMB |
| title_full_unstemmed | Non‑small cell lung cancer carrying PBRM1 mutation suggests an immunologically cold phenotype leading to immunotherapy failure even with high TMB |
| title_short | Non‑small cell lung cancer carrying PBRM1 mutation suggests an immunologically cold phenotype leading to immunotherapy failure even with high TMB |
| title_sort | non small cell lung cancer carrying pbrm1 mutation suggests an immunologically cold phenotype leading to immunotherapy failure even with high tmb |
| url | https://doi.org/10.1038/s41598-022-25050-3 |
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