Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma
Abstract Background Adrenocortical carcinoma (ACC) is a highly malignant urologic cancer and tends to metastasize. Although immune checkpoint inhibitors (ICIs) bring a glimmer of light to conquer ACC, only a fraction of patients have benefit from ICIs treatment. It is well known that tumor mutationa...
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| Format: | Article |
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BMC
2022-05-01
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| Series: | BMC Endocrine Disorders |
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| Online Access: | https://doi.org/10.1186/s12902-022-01017-3 |
| _version_ | 1818211396412768256 |
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| author | Fangshi Xu Yibing Guan Peng Zhang Li Xue Yubo Ma Mei Gao Tie Chong Bin-Cheng Ren |
| author_facet | Fangshi Xu Yibing Guan Peng Zhang Li Xue Yubo Ma Mei Gao Tie Chong Bin-Cheng Ren |
| author_sort | Fangshi Xu |
| collection | DOAJ |
| description | Abstract Background Adrenocortical carcinoma (ACC) is a highly malignant urologic cancer and tends to metastasize. Although immune checkpoint inhibitors (ICIs) bring a glimmer of light to conquer ACC, only a fraction of patients have benefit from ICIs treatment. It is well known that tumor mutational burden (TMB) is closely associated with the efficacy and response rate of immunotherapy. However, its roles in ACC were not investigated. Methods Using somatic mutations data of 92 ACC samples in TCGA database, we calculated their TMB values by the ‘maftools’ package in R software (Ver 3.6.3). To explore the roles of TMB in ICIs therapy, we have addressed this issue from three perspectives. First, the effects of TMB levels on tumor immune microenvironment (TIM) were analyzed through CIBERSORT algorithm, ssGSEA method and TIMER web server. Second, we investigated the expressive correlations between TMB level and five pivotal immune checkpoints based on Pearson coefficient. Third, the difference in TIDE score between high- and low-TMB groups was compared. The prognostic value of TMB was also evaluated. Besides, GSEA was performed to determine the changes in the activities of signaling pathways caused by TMB. Results TMB values in ACC samples were not high. The average of total mutation counts in each sample was only 21.5. High TMB could lead metabolic reprogramming and poor survival outcomes. However, it was unable to affect the infiltration levels of lymphocytes, and failed to facilitate the activities of immune-related pathways. Regarding immune checkpoints (ICs), only PD-L1 upregulation could result in a good prognosis, and TMB level did not correlate with the expressions of other ICs except for LAG3. There was no significant difference in TIDE score between high- and low-TMB groups. Combining the present results and previous study, we speculated that inadequate stimulation for neoantigens formation, intrinsic immune-resistance and special genomic alterations were three possible reasons for TMB limiting functions in TIM and ICIs. Besides, TMB was toughly applied in clinical practice due to its high cost of determination and non-universal definition of high TMB. Conclusions TMB presents limiting effects on prediction for ICIs efficacy and prognostic assessment for ACC patients. |
| first_indexed | 2024-12-12T05:31:50Z |
| format | Article |
| id | doaj.art-8e1853e2f1364c00a8ce1be6102522cb |
| institution | Directory Open Access Journal |
| issn | 1472-6823 |
| language | English |
| last_indexed | 2024-12-12T05:31:50Z |
| publishDate | 2022-05-01 |
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| series | BMC Endocrine Disorders |
| spelling | doaj.art-8e1853e2f1364c00a8ce1be6102522cb2022-12-22T00:36:17ZengBMCBMC Endocrine Disorders1472-68232022-05-0122111410.1186/s12902-022-01017-3Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinomaFangshi Xu0Yibing Guan1Peng Zhang2Li Xue3Yubo Ma4Mei Gao5Tie Chong6Bin-Cheng Ren7Department of Medicine, Xi’an Jiaotong UniversityDepartment of Medicine, Xi’an Jiaotong UniversityDepartment of Urology, The Second Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The Second Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Medicine, Xi’an Jiaotong UniversityDepartment of Urology, The Second Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Urology, The Second Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Rheumatology and Immunology, The Second Affiliated Hospital of Xi’an Jiaotong UniversityAbstract Background Adrenocortical carcinoma (ACC) is a highly malignant urologic cancer and tends to metastasize. Although immune checkpoint inhibitors (ICIs) bring a glimmer of light to conquer ACC, only a fraction of patients have benefit from ICIs treatment. It is well known that tumor mutational burden (TMB) is closely associated with the efficacy and response rate of immunotherapy. However, its roles in ACC were not investigated. Methods Using somatic mutations data of 92 ACC samples in TCGA database, we calculated their TMB values by the ‘maftools’ package in R software (Ver 3.6.3). To explore the roles of TMB in ICIs therapy, we have addressed this issue from three perspectives. First, the effects of TMB levels on tumor immune microenvironment (TIM) were analyzed through CIBERSORT algorithm, ssGSEA method and TIMER web server. Second, we investigated the expressive correlations between TMB level and five pivotal immune checkpoints based on Pearson coefficient. Third, the difference in TIDE score between high- and low-TMB groups was compared. The prognostic value of TMB was also evaluated. Besides, GSEA was performed to determine the changes in the activities of signaling pathways caused by TMB. Results TMB values in ACC samples were not high. The average of total mutation counts in each sample was only 21.5. High TMB could lead metabolic reprogramming and poor survival outcomes. However, it was unable to affect the infiltration levels of lymphocytes, and failed to facilitate the activities of immune-related pathways. Regarding immune checkpoints (ICs), only PD-L1 upregulation could result in a good prognosis, and TMB level did not correlate with the expressions of other ICs except for LAG3. There was no significant difference in TIDE score between high- and low-TMB groups. Combining the present results and previous study, we speculated that inadequate stimulation for neoantigens formation, intrinsic immune-resistance and special genomic alterations were three possible reasons for TMB limiting functions in TIM and ICIs. Besides, TMB was toughly applied in clinical practice due to its high cost of determination and non-universal definition of high TMB. Conclusions TMB presents limiting effects on prediction for ICIs efficacy and prognostic assessment for ACC patients.https://doi.org/10.1186/s12902-022-01017-3Tumor mutational burdenAdrenocortical carcinomaImmune checkpoint inhibitorsImmune microenvironmentPrognosis |
| spellingShingle | Fangshi Xu Yibing Guan Peng Zhang Li Xue Yubo Ma Mei Gao Tie Chong Bin-Cheng Ren Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma BMC Endocrine Disorders Tumor mutational burden Adrenocortical carcinoma Immune checkpoint inhibitors Immune microenvironment Prognosis |
| title | Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma |
| title_full | Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma |
| title_fullStr | Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma |
| title_full_unstemmed | Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma |
| title_short | Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma |
| title_sort | tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma |
| topic | Tumor mutational burden Adrenocortical carcinoma Immune checkpoint inhibitors Immune microenvironment Prognosis |
| url | https://doi.org/10.1186/s12902-022-01017-3 |
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