Tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma: post-hoc analysis of a single center, phase 2 study
Background Neoadjuvant chemoimmunotherapy has a promising effect on locally advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers robustly predicting therapeutic response are still lacking.Methods Formalin-fixed and paraffin-embedded pre-neoadjuvant chemoimmunotherapy biop...
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BMJ Publishing Group
2024-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/8/e008942.full |
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| author | Qian Li Tingting Feng Jing Zhu Chang Yu Ying Yang Qixun Chen Dan Su Xiaotian Zhang Changbin Zhu Rui Zhu Tingting Lu Liwei Xu Lisha Ying Canming Wang Weiming Xu Jinchao Wang Minran Huang Chenyang Xu Jiaoyue Jin |
| author_facet | Qian Li Tingting Feng Jing Zhu Chang Yu Ying Yang Qixun Chen Dan Su Xiaotian Zhang Changbin Zhu Rui Zhu Tingting Lu Liwei Xu Lisha Ying Canming Wang Weiming Xu Jinchao Wang Minran Huang Chenyang Xu Jiaoyue Jin |
| author_sort | Qian Li |
| collection | DOAJ |
| description | Background Neoadjuvant chemoimmunotherapy has a promising effect on locally advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers robustly predicting therapeutic response are still lacking.Methods Formalin-fixed and paraffin-embedded pre-neoadjuvant chemoimmunotherapy biopsy samples from locally advanced ESCC patients were collected. Cohort 1 composed of 66 locally advanced ESCC patients from a prospective clinical trial (NCT04506138) received two cycles of camrelizumab in combination with nab-paclitaxel and carboplatin every 3 weeks. Cohort 2 included 48 patients receiving various types of immune checkpoint inhibitors with (nab-)paclitaxel and platinum-based chemotherapy as neoadjuvant therapy. Cohort 3 consisted of 27 ESCC patients receiving neoadjuvant treatment of toripalimab with chemotherapy and was used as the external validation dataset. Targeted RNA sequencing, immunohistochemistry for programmed death ligand 1 (PD-L1), and multiplex immunofluorescence (mIF) imaging were performed.Results Integration of targeted RNA sequencing, PD-L1 immunohistochemistry, and mIF revealed a significant immune-suppressive microenvironment with higher neutrophil infiltration, enriched TGF-β, and cell cycle pathways in non-pathological complete response (non-pCR) patients. NK, activated CD4+ T cell infiltration, interferon-gamma, antigen processing and presentation, and other immune response signatures were significantly associated with pCR. Based on discovered tumor microenvironmental characteristics and their closely related genes were screened. Consequently, a seven-gene neoadjuvant chemoimmunotherapy risk prediction signature (NCIRPs) model, was constructed. In addition to cohort 1, this model alone or with PD-L1-combined positive score (CPS) demonstrated a higher prediction accuracy of pathological response than PD-L1 CPS or other routinely used immune signatures, such as IFN-γ, in cohorts 2 and 3. Neither prognostic association nor correlation with response to chemoradiotherapy was observed in The Cancer Genome Atlas Program ESCC dataset or in ESCC patients in the neoadjuvant chemoradiotherapy cohort (cohort 4).Conclusion The NCIRPs model that was developed and validated using treatment-naïve endoscopic samples from the largest ESCC neoadjuvant chemoimmunotherapy dataset represents a robust and clinically meaningful approach to select a putative responder for neoadjuvant chemoimmunotherapy in locally advanced ESCC patients. |
| format | Article |
| id | doaj-art-5175472c9774416ebbcc62faf1771cfc |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-5175472c9774416ebbcc62faf1771cfc2024-11-10T06:00:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-08-0112810.1136/jitc-2024-008942Tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma: post-hoc analysis of a single center, phase 2 studyQian Li0Tingting Feng1Jing Zhu2Chang Yu3Ying Yang4Qixun Chen5Dan Su6Xiaotian Zhang7Changbin Zhu8Rui Zhu9Tingting Lu10Liwei Xu11Lisha Ying12Canming Wang13Weiming Xu14Jinchao Wang15Minran Huang16Chenyang Xu17Jiaoyue Jin18Medical Department, Amoy Diagnostics Co Ltd, Xiamen, Fujian, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pulmonary Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaMedical Department, Amoy Diagnostics Co Ltd, Xiamen, Fujian, ChinaMedical Department, Amoy Diagnostics Co Ltd, Xiamen, Fujian, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pulmonary Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaCancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pathology, Taizhou Hospital of Zhejiang Province affiliated with Wenzhou Medical University, Taizhou, Zhejiang, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaDepartment of Pathology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, ChinaBackground Neoadjuvant chemoimmunotherapy has a promising effect on locally advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers robustly predicting therapeutic response are still lacking.Methods Formalin-fixed and paraffin-embedded pre-neoadjuvant chemoimmunotherapy biopsy samples from locally advanced ESCC patients were collected. Cohort 1 composed of 66 locally advanced ESCC patients from a prospective clinical trial (NCT04506138) received two cycles of camrelizumab in combination with nab-paclitaxel and carboplatin every 3 weeks. Cohort 2 included 48 patients receiving various types of immune checkpoint inhibitors with (nab-)paclitaxel and platinum-based chemotherapy as neoadjuvant therapy. Cohort 3 consisted of 27 ESCC patients receiving neoadjuvant treatment of toripalimab with chemotherapy and was used as the external validation dataset. Targeted RNA sequencing, immunohistochemistry for programmed death ligand 1 (PD-L1), and multiplex immunofluorescence (mIF) imaging were performed.Results Integration of targeted RNA sequencing, PD-L1 immunohistochemistry, and mIF revealed a significant immune-suppressive microenvironment with higher neutrophil infiltration, enriched TGF-β, and cell cycle pathways in non-pathological complete response (non-pCR) patients. NK, activated CD4+ T cell infiltration, interferon-gamma, antigen processing and presentation, and other immune response signatures were significantly associated with pCR. Based on discovered tumor microenvironmental characteristics and their closely related genes were screened. Consequently, a seven-gene neoadjuvant chemoimmunotherapy risk prediction signature (NCIRPs) model, was constructed. In addition to cohort 1, this model alone or with PD-L1-combined positive score (CPS) demonstrated a higher prediction accuracy of pathological response than PD-L1 CPS or other routinely used immune signatures, such as IFN-γ, in cohorts 2 and 3. Neither prognostic association nor correlation with response to chemoradiotherapy was observed in The Cancer Genome Atlas Program ESCC dataset or in ESCC patients in the neoadjuvant chemoradiotherapy cohort (cohort 4).Conclusion The NCIRPs model that was developed and validated using treatment-naïve endoscopic samples from the largest ESCC neoadjuvant chemoimmunotherapy dataset represents a robust and clinically meaningful approach to select a putative responder for neoadjuvant chemoimmunotherapy in locally advanced ESCC patients.https://jitc.bmj.com/content/12/8/e008942.full |
| spellingShingle | Qian Li Tingting Feng Jing Zhu Chang Yu Ying Yang Qixun Chen Dan Su Xiaotian Zhang Changbin Zhu Rui Zhu Tingting Lu Liwei Xu Lisha Ying Canming Wang Weiming Xu Jinchao Wang Minran Huang Chenyang Xu Jiaoyue Jin Tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma: post-hoc analysis of a single center, phase 2 study Journal for ImmunoTherapy of Cancer |
| title | Tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma: post-hoc analysis of a single center, phase 2 study |
| title_full | Tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma: post-hoc analysis of a single center, phase 2 study |
| title_fullStr | Tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma: post-hoc analysis of a single center, phase 2 study |
| title_full_unstemmed | Tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma: post-hoc analysis of a single center, phase 2 study |
| title_short | Tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma: post-hoc analysis of a single center, phase 2 study |
| title_sort | tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma post hoc analysis of a single center phase 2 study |
| url | https://jitc.bmj.com/content/12/8/e008942.full |
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