Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer
Abstract Objectives The impact of cGAS/STING tumor expression on PD-1/L1 inhibitor efficacy and the tumor microenvironment remain to be elucidated. Methods In a post-hoc analysis of a prospective biomarker study with 106 advanced NSCLC patients treated with PD-1/L1 inhibitors from December 2015 to S...
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Springer
2024-11-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-024-03861-9 |
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| author | Yuichi Ozawa Yasuhiro Koh Ryota Shibaki Yuhei Harutani Hiroaki Akamatsu Atsushi Hayata Takeya Sugimoto Yuka Kitamura Junya Fukuoka Masanori Nakanishi Nobuyuki Yamamoto |
| author_facet | Yuichi Ozawa Yasuhiro Koh Ryota Shibaki Yuhei Harutani Hiroaki Akamatsu Atsushi Hayata Takeya Sugimoto Yuka Kitamura Junya Fukuoka Masanori Nakanishi Nobuyuki Yamamoto |
| author_sort | Yuichi Ozawa |
| collection | DOAJ |
| description | Abstract Objectives The impact of cGAS/STING tumor expression on PD-1/L1 inhibitor efficacy and the tumor microenvironment remain to be elucidated. Methods In a post-hoc analysis of a prospective biomarker study with 106 advanced NSCLC patients treated with PD-1/L1 inhibitors from December 2015 to September 2018, tumor tissue before treatment from 68 patients was analyzed. cGAS and STING expression were measured using immunohistochemical staining and H-scores. Additionally, 40 serum proteins were quantified before and 4–6 weeks after treatment initiation. Results Median cGAS and STING H-scores were 220 (range, 5–300) and 190 (range, 0–300), respectively. There were no differences in cGAS or STING H-scores between the high (tumor proportion score [TPS] ≥ 50) and low (TPS < 50) PD-L1groups (p = 0.990 and 0.283, respectively). Unexpectedly, patients with high cGAS (H-score ≥ 220) demonstrated significantly shorter progression-free survival (PFS) of PD-1/L1 inhibitors when the PD-L1 TPS was high (median PFS: 143 days vs. not reached; p = 0.028); PFS at 18 months was 7% and 53% in the high and low cGAS groups, respectively while STING expression did not impact PFS. In serum protein analyses, high cGAS H-score was associated with significantly higher TGF-β1 and TGF-β2 before PD-1/L1 inhibition (47.5 vs. 22.3 ng/l, p = 0.023; 2118 vs. 882 pg/ml, p = 0.037); additionally, the cGAS H-score significantly correlated with TGF-β1 (r = 0.451, p = 0.009) and TGF-β2 (r = 0.375, p = 0.031) basal levels. Conclusion cGAS expression, but not STING, predicts poor PD-1/L1 inhibitor efficacy in NSCLC with high PD-L1, potentially due to a TGF-β-mediated immunosuppressive environment (UMIN000024414). |
| format | Article |
| id | doaj-art-6dd19f548e314b2484a913542451c57c |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Springer |
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| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-6dd19f548e314b2484a913542451c57c2025-02-02T12:26:49ZengSpringerCancer Immunology, Immunotherapy1432-08512024-11-0174111010.1007/s00262-024-03861-9Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancerYuichi Ozawa0Yasuhiro Koh1Ryota Shibaki2Yuhei Harutani3Hiroaki Akamatsu4Atsushi Hayata5Takeya Sugimoto6Yuka Kitamura7Junya Fukuoka8Masanori Nakanishi9Nobuyuki Yamamoto10Internal Medicine III, Wakayama Medical UniversityInternal Medicine III, Wakayama Medical UniversityInternal Medicine III, Wakayama Medical UniversityInternal Medicine III, Wakayama Medical UniversityInternal Medicine III, Wakayama Medical UniversityInternal Medicine III, Wakayama Medical UniversityInternal Medicine III, Wakayama Medical UniversityDepartment of Pathology, Nagasaki University Graduate School of Biomedical SciencesDepartment of Pathology, Nagasaki University Graduate School of Biomedical SciencesInternal Medicine III, Wakayama Medical UniversityInternal Medicine III, Wakayama Medical UniversityAbstract Objectives The impact of cGAS/STING tumor expression on PD-1/L1 inhibitor efficacy and the tumor microenvironment remain to be elucidated. Methods In a post-hoc analysis of a prospective biomarker study with 106 advanced NSCLC patients treated with PD-1/L1 inhibitors from December 2015 to September 2018, tumor tissue before treatment from 68 patients was analyzed. cGAS and STING expression were measured using immunohistochemical staining and H-scores. Additionally, 40 serum proteins were quantified before and 4–6 weeks after treatment initiation. Results Median cGAS and STING H-scores were 220 (range, 5–300) and 190 (range, 0–300), respectively. There were no differences in cGAS or STING H-scores between the high (tumor proportion score [TPS] ≥ 50) and low (TPS < 50) PD-L1groups (p = 0.990 and 0.283, respectively). Unexpectedly, patients with high cGAS (H-score ≥ 220) demonstrated significantly shorter progression-free survival (PFS) of PD-1/L1 inhibitors when the PD-L1 TPS was high (median PFS: 143 days vs. not reached; p = 0.028); PFS at 18 months was 7% and 53% in the high and low cGAS groups, respectively while STING expression did not impact PFS. In serum protein analyses, high cGAS H-score was associated with significantly higher TGF-β1 and TGF-β2 before PD-1/L1 inhibition (47.5 vs. 22.3 ng/l, p = 0.023; 2118 vs. 882 pg/ml, p = 0.037); additionally, the cGAS H-score significantly correlated with TGF-β1 (r = 0.451, p = 0.009) and TGF-β2 (r = 0.375, p = 0.031) basal levels. Conclusion cGAS expression, but not STING, predicts poor PD-1/L1 inhibitor efficacy in NSCLC with high PD-L1, potentially due to a TGF-β-mediated immunosuppressive environment (UMIN000024414).https://doi.org/10.1007/s00262-024-03861-9Lung cancercGASSTINGTGF-bPD-L1Immune checkpoint inhibitor |
| spellingShingle | Yuichi Ozawa Yasuhiro Koh Ryota Shibaki Yuhei Harutani Hiroaki Akamatsu Atsushi Hayata Takeya Sugimoto Yuka Kitamura Junya Fukuoka Masanori Nakanishi Nobuyuki Yamamoto Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer Cancer Immunology, Immunotherapy Lung cancer cGAS STING TGF-b PD-L1 Immune checkpoint inhibitor |
| title | Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer |
| title_full | Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer |
| title_fullStr | Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer |
| title_full_unstemmed | Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer |
| title_short | Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer |
| title_sort | uncovering the role of tumor cgas expression in predicting response to pd 1 l1 inhibitors in non small cell lung cancer |
| topic | Lung cancer cGAS STING TGF-b PD-L1 Immune checkpoint inhibitor |
| url | https://doi.org/10.1007/s00262-024-03861-9 |
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