Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer
Background Programmed cell death ligand 1 (PD-L1) expressed on tumor and immune cells are both associated with the response to programmed cell death 1 (PD-1) pathway blockade therapy. Here, we examine the role of CD8+PD-L1+ tumor-infiltrating lymphocyte (Tils) in the tumor microenvironment of non-sm...
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BMJ Publishing Group
2021-06-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/6/e002356.full |
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| author | Yang Wang Jun Liu Han Wang Yun Chen Hao Peng Henghui Zhang Libin Zhang Yanhui Chen Zheyuan Xu Sixing Li Hongli Luo Lijia Wu |
| author_facet | Yang Wang Jun Liu Han Wang Yun Chen Hao Peng Henghui Zhang Libin Zhang Yanhui Chen Zheyuan Xu Sixing Li Hongli Luo Lijia Wu |
| author_sort | Yang Wang |
| collection | DOAJ |
| description | Background Programmed cell death ligand 1 (PD-L1) expressed on tumor and immune cells are both associated with the response to programmed cell death 1 (PD-1) pathway blockade therapy. Here, we examine the role of CD8+PD-L1+ tumor-infiltrating lymphocyte (Tils) in the tumor microenvironment of non-small cell lung cancer (NSCLC).Methods Tumor tissue samples of a total of 378 patients from two NSCLC cohorts were collected retrospectively. Tumor genetic variations were measured by targeted next-generation sequencing of 543 oncogenes. Tils were assessed by multiplex immunohistochemistry assay. Correlations among Tils, tumor genetic variations, and clinicopathological characteristics were analyzed.Results The levels of CD8+PD-L1+ Tils varied in NSCLC tumor tissues. Tumor samples with high CD8+PD-L1+ Tils had higher levels of CD8+ Tils, CD68+ macrophages, PD-L1+ tumor cells, PD-1+ Tils, and CD163+ M2-type macrophages, and also had a higher tumor mutation burden, all of which collectively constituted a typically hot but immunosuppressive tumor microenvironment. Therefore, in a non-immunotherapy cohort, we observed that the higher the CD8+PD-L1+ Tils level in the tumor tissue, the worse the prognosis (progression-free survival; cohort A, stage I–II tumor; p=0.005). Contrarily, in an immunotherapy cohort, where the immune suppression was blocked by anti-PD-1 treatment, the higher the CD8+PD-L1+ Tils level, the better the response to the anti-PD-1 treatment (complete response/partial response vs stable disease/progressive disease; cohort B; p=0.0337).Conclusions CD8+PD-L1+ Tils may be an indicator of the hot but immunosuppressive tumor microenvironment which is related to a high tumor mutation burden. PD-1 pathway blockade therapy can help to mitigate this immunosuppression and obtain better curative effects. |
| format | Article |
| id | doaj-art-e439bfec4f494e1bb940bf0d2a69c631 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-e439bfec4f494e1bb940bf0d2a69c6312024-11-08T21:40:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-06-019610.1136/jitc-2021-002356Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancerYang Wang0Jun Liu1Han Wang2Yun Chen3Hao Peng4Henghui Zhang5Libin Zhang6Yanhui Chen7Zheyuan Xu8Sixing Li9Hongli Luo10Lijia Wu11Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China4Providence Therapeutics Holdings, Inc., Toronto, ON, Canada1 Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China2 Department of Immunology, Nanjing Medical University, Nanjing, China1 Department of Thoracic Surgery, The First People`s Hospital of Yunnan Province, Kunming, Yunnan, China4 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, ChinaVascular Surgery, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China2 Department of Medicine, Genecast Biotechnology Co., Ltd, Wuxi, Jiangsu, China1 Department of Thoracic Surgery, The First People`s Hospital of Yunnan Province, Kunming, Yunnan, ChinaDepartment of Intensive Care Unit, Liuzhou Workers` Hospital, Liuzhou, China1 Department of Pharmacy, the Affiliated Hospital of Southwest Medical University, Luzhou, People`s Republic of China3 Department of Bioinformatics, Genecast Biotechnology Co., Ltd, Wuxi, Jiangsu, ChinaBackground Programmed cell death ligand 1 (PD-L1) expressed on tumor and immune cells are both associated with the response to programmed cell death 1 (PD-1) pathway blockade therapy. Here, we examine the role of CD8+PD-L1+ tumor-infiltrating lymphocyte (Tils) in the tumor microenvironment of non-small cell lung cancer (NSCLC).Methods Tumor tissue samples of a total of 378 patients from two NSCLC cohorts were collected retrospectively. Tumor genetic variations were measured by targeted next-generation sequencing of 543 oncogenes. Tils were assessed by multiplex immunohistochemistry assay. Correlations among Tils, tumor genetic variations, and clinicopathological characteristics were analyzed.Results The levels of CD8+PD-L1+ Tils varied in NSCLC tumor tissues. Tumor samples with high CD8+PD-L1+ Tils had higher levels of CD8+ Tils, CD68+ macrophages, PD-L1+ tumor cells, PD-1+ Tils, and CD163+ M2-type macrophages, and also had a higher tumor mutation burden, all of which collectively constituted a typically hot but immunosuppressive tumor microenvironment. Therefore, in a non-immunotherapy cohort, we observed that the higher the CD8+PD-L1+ Tils level in the tumor tissue, the worse the prognosis (progression-free survival; cohort A, stage I–II tumor; p=0.005). Contrarily, in an immunotherapy cohort, where the immune suppression was blocked by anti-PD-1 treatment, the higher the CD8+PD-L1+ Tils level, the better the response to the anti-PD-1 treatment (complete response/partial response vs stable disease/progressive disease; cohort B; p=0.0337).Conclusions CD8+PD-L1+ Tils may be an indicator of the hot but immunosuppressive tumor microenvironment which is related to a high tumor mutation burden. PD-1 pathway blockade therapy can help to mitigate this immunosuppression and obtain better curative effects.https://jitc.bmj.com/content/9/6/e002356.full |
| spellingShingle | Yang Wang Jun Liu Han Wang Yun Chen Hao Peng Henghui Zhang Libin Zhang Yanhui Chen Zheyuan Xu Sixing Li Hongli Luo Lijia Wu Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer Journal for ImmunoTherapy of Cancer |
| title | Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer |
| title_full | Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer |
| title_fullStr | Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer |
| title_full_unstemmed | Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer |
| title_short | Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer |
| title_sort | massive pd l1 and cd8 double positive tils characterize an immunosuppressive microenvironment with high mutational burden in lung cancer |
| url | https://jitc.bmj.com/content/9/6/e002356.full |
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