Alterations in TP53 Are a Potential Biomarker of Bladder Cancer Patients Who Benefit From Immune Checkpoint Inhibition
In recent years, immune checkpoint inhibitors (ICIs) targeting CTLA-4 or PD1/PDL1 have achieved remarkable success in the treatment of bladder cancer (BLCA), but only a few patients have shown durable clinical benefits. The prognostic role of a mutant form of the tumor suppressor gene TP53 (TP53-MT)...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2020-12-01
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| Series: | Cancer Control |
| Online Access: | https://doi.org/10.1177/1073274820976665 |
| _version_ | 1827893070834696192 |
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| author | Qiong Lyu MD Anqi Lin MD Manming Cao MD Abai Xu MD Peng Luo MD Jian Zhang MD |
| author_facet | Qiong Lyu MD Anqi Lin MD Manming Cao MD Abai Xu MD Peng Luo MD Jian Zhang MD |
| author_sort | Qiong Lyu MD |
| collection | DOAJ |
| description | In recent years, immune checkpoint inhibitors (ICIs) targeting CTLA-4 or PD1/PDL1 have achieved remarkable success in the treatment of bladder cancer (BLCA), but only a few patients have shown durable clinical benefits. The prognostic role of a mutant form of the tumor suppressor gene TP53 (TP53-MT) in predicting the efficacy of ICIs is highly controversial; therefore, in this study, we obtained data for 210 patients from an immunotherapy cohort, 412 patients from The Cancer Genome Atlas (TCGA)-BLCA cohort and 18 BLCA cell lines from Genomics of Drug Sensitivity in Cancer (GDSC), and we performed integrated bioinformatic analysis to explore the relationships between TP53-MT and clinical benefits derived from ICI treatment and the underlying mechanisms. We conclude that TP53-MT is a potential indicator of a relatively good response to ICIs and associated with prolonged overall survival (OS) (log-rank test, hazard ratio (HR) = 0.65 [95% confidence interval (CI), 0.44-0.99], p = 0.041). Through integrated analysis with several platforms, we found that TP53-MT patients were more likely to benefit from ICIs than wild-type P53 (TP53-WT) patients, which may be the result of 2 major mechanisms. First, the patients with TP53-MT showed stronger tumor antigenicity and tumor antigen presentation, as indicated by a higher tumor mutational load, a higher neoantigen load and increased expression of MHC; second, the antitumor immunity preexisting in tumors was stronger in samples with TP53-MT than in those with TP53-WT, including enrichment of interferon-gamma, positive regulation of TNF secretion pathways and increased expression of some immunostimulatory molecules, such as CXCL9 and CXCL10. This study provided some clues for identifying patients who would potentially benefit from ICIs at the somatic genomic level, developing new indications for targeted second-generation sequencing and promoting the development of precision medicine. |
| first_indexed | 2024-03-12T21:48:44Z |
| format | Article |
| id | doaj.art-ed277d9f97df48e2b1246b4fe0166fe5 |
| institution | Directory Open Access Journal |
| issn | 1073-2748 |
| language | English |
| last_indexed | 2024-03-12T21:48:44Z |
| publishDate | 2020-12-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Cancer Control |
| spelling | doaj.art-ed277d9f97df48e2b1246b4fe0166fe52023-07-26T07:05:55ZengSAGE PublishingCancer Control1073-27482020-12-012710.1177/1073274820976665Alterations in TP53 Are a Potential Biomarker of Bladder Cancer Patients Who Benefit From Immune Checkpoint InhibitionQiong Lyu MD0Anqi Lin MD1Manming Cao MD2Abai Xu MD3Peng Luo MD4Jian Zhang MD5 Department of Oncology, , Guang Zhou, China Department of Oncology, , Guang Zhou, China Department of Oncology, , Guang Zhou, China Department of Urology, , Guangzhou, China Department of Oncology, , Guang Zhou, China Department of Oncology, , Guang Zhou, ChinaIn recent years, immune checkpoint inhibitors (ICIs) targeting CTLA-4 or PD1/PDL1 have achieved remarkable success in the treatment of bladder cancer (BLCA), but only a few patients have shown durable clinical benefits. The prognostic role of a mutant form of the tumor suppressor gene TP53 (TP53-MT) in predicting the efficacy of ICIs is highly controversial; therefore, in this study, we obtained data for 210 patients from an immunotherapy cohort, 412 patients from The Cancer Genome Atlas (TCGA)-BLCA cohort and 18 BLCA cell lines from Genomics of Drug Sensitivity in Cancer (GDSC), and we performed integrated bioinformatic analysis to explore the relationships between TP53-MT and clinical benefits derived from ICI treatment and the underlying mechanisms. We conclude that TP53-MT is a potential indicator of a relatively good response to ICIs and associated with prolonged overall survival (OS) (log-rank test, hazard ratio (HR) = 0.65 [95% confidence interval (CI), 0.44-0.99], p = 0.041). Through integrated analysis with several platforms, we found that TP53-MT patients were more likely to benefit from ICIs than wild-type P53 (TP53-WT) patients, which may be the result of 2 major mechanisms. First, the patients with TP53-MT showed stronger tumor antigenicity and tumor antigen presentation, as indicated by a higher tumor mutational load, a higher neoantigen load and increased expression of MHC; second, the antitumor immunity preexisting in tumors was stronger in samples with TP53-MT than in those with TP53-WT, including enrichment of interferon-gamma, positive regulation of TNF secretion pathways and increased expression of some immunostimulatory molecules, such as CXCL9 and CXCL10. This study provided some clues for identifying patients who would potentially benefit from ICIs at the somatic genomic level, developing new indications for targeted second-generation sequencing and promoting the development of precision medicine.https://doi.org/10.1177/1073274820976665 |
| spellingShingle | Qiong Lyu MD Anqi Lin MD Manming Cao MD Abai Xu MD Peng Luo MD Jian Zhang MD Alterations in TP53 Are a Potential Biomarker of Bladder Cancer Patients Who Benefit From Immune Checkpoint Inhibition Cancer Control |
| title | Alterations in TP53 Are a Potential Biomarker of Bladder Cancer Patients Who Benefit From Immune Checkpoint Inhibition |
| title_full | Alterations in TP53 Are a Potential Biomarker of Bladder Cancer Patients Who Benefit From Immune Checkpoint Inhibition |
| title_fullStr | Alterations in TP53 Are a Potential Biomarker of Bladder Cancer Patients Who Benefit From Immune Checkpoint Inhibition |
| title_full_unstemmed | Alterations in TP53 Are a Potential Biomarker of Bladder Cancer Patients Who Benefit From Immune Checkpoint Inhibition |
| title_short | Alterations in TP53 Are a Potential Biomarker of Bladder Cancer Patients Who Benefit From Immune Checkpoint Inhibition |
| title_sort | alterations in tp53 are a potential biomarker of bladder cancer patients who benefit from immune checkpoint inhibition |
| url | https://doi.org/10.1177/1073274820976665 |
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