POLQ identifies a better response subset to immunotherapy in muscle‐invasive bladder cancer with high PD‐L1
Abstract Background Though programmed cell death‐ligand 1 (PD‐L1) has been used in predicting the efficacy of immune checkpoint blockade (ICB), it is insufficient as a single biomarker. As a key effector of an intrinsically mutagenic microhomology‐mediated end joining (MMEJ) pathway, DNA polymerase...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-02-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.6962 |
| _version_ | 1797265476720525312 |
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| author | Ge Liu Kaifeng Jin Zhaopei Liu Xiaohe Su Ziyue Xu Bingyu Li Jingtong Xu Yuan Chang Yiwei Wang Yu Zhu Le Xu Jiejie Xu Zewei Wang Hailong Liu Weijuan Zhang |
| author_facet | Ge Liu Kaifeng Jin Zhaopei Liu Xiaohe Su Ziyue Xu Bingyu Li Jingtong Xu Yuan Chang Yiwei Wang Yu Zhu Le Xu Jiejie Xu Zewei Wang Hailong Liu Weijuan Zhang |
| author_sort | Ge Liu |
| collection | DOAJ |
| description | Abstract Background Though programmed cell death‐ligand 1 (PD‐L1) has been used in predicting the efficacy of immune checkpoint blockade (ICB), it is insufficient as a single biomarker. As a key effector of an intrinsically mutagenic microhomology‐mediated end joining (MMEJ) pathway, DNA polymerase theta (POLQ) was overexpressed in various malignancies, whose expression might have an influence on genomic stability, therefore altering the sensitivity to chemotherapy and immunotherapy. Methods A total of 1304 patients with muscle‐invasive bladder cancer (MIBC) from six independent cohorts were included in this study. The Zhongshan Hospital (ZSHS) cohort (n = 134), The Cancer Genome Atlas (TCGA) cohort (n = 391), and the Neo‐cohort (n = 148) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n = 234) and the UNC‐108 cohort (n = 89) were used for the assessment of immunotherapeutic response. In addition, the relationship between POLQ and the immune microenvironment was assessed, and GSE32894 (n = 308) was used only for the evaluation of the immune microenvironment. Results We identified POLQhigh PD‐L1high patients could benefit more from immunotherapy and platinum‐based chemotherapy. Further analysis revealed that high POLQ expression was linked to chromosome instability and higher tumor mutational burden (TMB), which might elicit the production of neoantigens. Further, high POLQ expression was associated with an active tumor immune microenvironment with abundant infiltration of immune effector cells and molecules. Conclusions The study demonstrated that high POLQ expression was correlated with chromosome instability and antitumor immune microenvironment in MIBC, and the combination of POLQ and PD‐L1 could be used as a superior companion biomarker for predicting the efficacy of immunotherapy. |
| first_indexed | 2024-04-25T00:45:24Z |
| format | Article |
| id | doaj.art-b1366ffacca3492f8c92d2ad430998fe |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-25T00:45:24Z |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-b1366ffacca3492f8c92d2ad430998fe2024-03-12T04:52:34ZengWileyCancer Medicine2045-76342024-02-01134n/an/a10.1002/cam4.6962POLQ identifies a better response subset to immunotherapy in muscle‐invasive bladder cancer with high PD‐L1Ge Liu0Kaifeng Jin1Zhaopei Liu2Xiaohe Su3Ziyue Xu4Bingyu Li5Jingtong Xu6Yuan Chang7Yiwei Wang8Yu Zhu9Le Xu10Jiejie Xu11Zewei Wang12Hailong Liu13Weijuan Zhang14NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences Fudan University Shanghai ChinaNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences Fudan University Shanghai ChinaNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences Fudan University Shanghai ChinaNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences Fudan University Shanghai ChinaNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences Fudan University Shanghai ChinaDepartment of Immunology, School of Basic Medical Sciences Fudan University Shanghai ChinaDepartment of Immunology, School of Basic Medical Sciences Fudan University Shanghai ChinaDepartment of Urology Fudan University Shanghai Cancer Center Shanghai ChinaDepartment of Urology, Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaDepartment of Urology Fudan University Shanghai Cancer Center Shanghai ChinaDepartment of Urology, Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaNHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences Fudan University Shanghai ChinaDepartment of Urology, Zhongshan Hospital Fudan University Shanghai ChinaDepartment of Urology, Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaDepartment of Immunology, School of Basic Medical Sciences Fudan University Shanghai ChinaAbstract Background Though programmed cell death‐ligand 1 (PD‐L1) has been used in predicting the efficacy of immune checkpoint blockade (ICB), it is insufficient as a single biomarker. As a key effector of an intrinsically mutagenic microhomology‐mediated end joining (MMEJ) pathway, DNA polymerase theta (POLQ) was overexpressed in various malignancies, whose expression might have an influence on genomic stability, therefore altering the sensitivity to chemotherapy and immunotherapy. Methods A total of 1304 patients with muscle‐invasive bladder cancer (MIBC) from six independent cohorts were included in this study. The Zhongshan Hospital (ZSHS) cohort (n = 134), The Cancer Genome Atlas (TCGA) cohort (n = 391), and the Neo‐cohort (n = 148) were included for the investigation of chemotherapeutic response. The IMvigor210 cohort (n = 234) and the UNC‐108 cohort (n = 89) were used for the assessment of immunotherapeutic response. In addition, the relationship between POLQ and the immune microenvironment was assessed, and GSE32894 (n = 308) was used only for the evaluation of the immune microenvironment. Results We identified POLQhigh PD‐L1high patients could benefit more from immunotherapy and platinum‐based chemotherapy. Further analysis revealed that high POLQ expression was linked to chromosome instability and higher tumor mutational burden (TMB), which might elicit the production of neoantigens. Further, high POLQ expression was associated with an active tumor immune microenvironment with abundant infiltration of immune effector cells and molecules. Conclusions The study demonstrated that high POLQ expression was correlated with chromosome instability and antitumor immune microenvironment in MIBC, and the combination of POLQ and PD‐L1 could be used as a superior companion biomarker for predicting the efficacy of immunotherapy.https://doi.org/10.1002/cam4.6962immunotherapymuscle‐invasive bladder cancerPD‐L1platinum‐based chemotherapyPOLQ |
| spellingShingle | Ge Liu Kaifeng Jin Zhaopei Liu Xiaohe Su Ziyue Xu Bingyu Li Jingtong Xu Yuan Chang Yiwei Wang Yu Zhu Le Xu Jiejie Xu Zewei Wang Hailong Liu Weijuan Zhang POLQ identifies a better response subset to immunotherapy in muscle‐invasive bladder cancer with high PD‐L1 Cancer Medicine immunotherapy muscle‐invasive bladder cancer PD‐L1 platinum‐based chemotherapy POLQ |
| title | POLQ identifies a better response subset to immunotherapy in muscle‐invasive bladder cancer with high PD‐L1 |
| title_full | POLQ identifies a better response subset to immunotherapy in muscle‐invasive bladder cancer with high PD‐L1 |
| title_fullStr | POLQ identifies a better response subset to immunotherapy in muscle‐invasive bladder cancer with high PD‐L1 |
| title_full_unstemmed | POLQ identifies a better response subset to immunotherapy in muscle‐invasive bladder cancer with high PD‐L1 |
| title_short | POLQ identifies a better response subset to immunotherapy in muscle‐invasive bladder cancer with high PD‐L1 |
| title_sort | polq identifies a better response subset to immunotherapy in muscle invasive bladder cancer with high pd l1 |
| topic | immunotherapy muscle‐invasive bladder cancer PD‐L1 platinum‐based chemotherapy POLQ |
| url | https://doi.org/10.1002/cam4.6962 |
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