Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis
Background: Although the lactate pathway has been reported to lead to immune escape through the inhibition of effector T cells, the cancer-intrinsic lactate signature has not been identified, and the immunotherapeutic efficacy and potential mechanism of the lactate signature are still unclear. Metho...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-12-01
|
| Series: | Heliyon |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024155223 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850244842107437056 |
|---|---|
| author | Shuiting Fu Jiachen Xu Chunming Wang Cheng Zhang Chengcheng Li Wenchuan Xie Guoqiang Wang Xin Zhu Yuyan Xu Yaohong Wen Jingyuan Pei Jun Yang Mingyang Tang Hongkun Tan Shangli Cai Lei Cai Mingxin Pan |
| author_facet | Shuiting Fu Jiachen Xu Chunming Wang Cheng Zhang Chengcheng Li Wenchuan Xie Guoqiang Wang Xin Zhu Yuyan Xu Yaohong Wen Jingyuan Pei Jun Yang Mingyang Tang Hongkun Tan Shangli Cai Lei Cai Mingxin Pan |
| author_sort | Shuiting Fu |
| collection | DOAJ |
| description | Background: Although the lactate pathway has been reported to lead to immune escape through the inhibition of effector T cells, the cancer-intrinsic lactate signature has not been identified, and the immunotherapeutic efficacy and potential mechanism of the lactate signature are still unclear. Methods: We defined a pan-cancer up-lactate score by comparing malignant tissues and normal tissues in the TCGA cohort. The immunotherapeutic efficacy was evaluated in non-small cell lung cancer (NSCLC), metastatic renal cancer (mRCC), bladder cancer (BLCA) and melanoma cohorts. The cancer cell-intrinsic mechanism to immune checkpoint inhibitors (ICIs) resistance was measured using single cell sequencing (scRNA-seq) data. Pathway activation was evaluated in the TCGA cohort and CPTAC cohort with transcriptomics and proteomics. The co-occurrence of up-lactate signature and mTOR signaling was determined by spatial transcriptomics of the tissue samples. Immunotherapy resistance and pathway regulation were validated in the in-house NSCLC cohort. Results: Patients with the high up-lactate scores had significantly short overall survival (OS) than those with the low up-lactate scores (p < 0.001) across multiple types of cancers. The up-regulated lactate signature exhibited higher expression in the malignant cells compared with stromal cells and immune cells in multiple scRNA-seq datasets. A high up-lactate score was associated with poor OS in NSCLC, mRCC, BLCA and melanoma patients who received anti-PD(L)1 antibody. The up-lactate score was higher in the responders of cancer cells, but not in immune cells and stromal cells compared with the non-responders (p < 0.05). Moreover, up-lactate score was positively correlated with mTOR signaling across multiple cancers. In patients with NSCLC who received anti-PD-1 antibody, higher up-lactate scores were associated with significantly shorter PFS compared to lower up-lactate scores (p < 0.001). Additionally, the up-lactate score was associated with cold tumor, and was positively correlated with mTOR signaling. Conclusion: Collectively, we defined a pan-cancer up-lactate signature, which is a feature of malignant cells and is associated with ICIs resistance. This reveals a coherent program with prognostic and predictive value that may be therapeutically targeted. |
| format | Article |
| id | doaj-art-7d3bc8d667ab416688a034b4a09ff527 |
| institution | OA Journals |
| issn | 2405-8440 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-7d3bc8d667ab416688a034b4a09ff5272025-08-20T01:59:38ZengElsevierHeliyon2405-84402024-12-011023e3949110.1016/j.heliyon.2024.e39491Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysisShuiting Fu0Jiachen Xu1Chunming Wang2Cheng Zhang3Chengcheng Li4Wenchuan Xie5Guoqiang Wang6Xin Zhu7Yuyan Xu8Yaohong Wen9Jingyuan Pei10Jun Yang11Mingyang Tang12Hongkun Tan13Shangli Cai14Lei Cai15Mingxin Pan16Department of Oral & Maxillofacial - Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, ChinaState Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Guangdong Provincial People's Hospital/Guangdong Provincial Academy of Medical Sciences, Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer, ChinaGeneral Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, ChinaGeneral Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, ChinaBurning Rock Biotech, Guangzhou, 510300, ChinaBurning Rock Biotech, Guangzhou, 510300, ChinaBurning Rock Biotech, Guangzhou, 510300, ChinaBurning Rock Biotech, Guangzhou, 510300, ChinaGeneral Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, ChinaGeneral Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, ChinaGeneral Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, ChinaGeneral Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, ChinaGeneral Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, ChinaGeneral Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, ChinaBurning Rock Biotech, Guangzhou, 510300, ChinaGeneral Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Corresponding author. General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Corresponding author. General Surgery Center, Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.Background: Although the lactate pathway has been reported to lead to immune escape through the inhibition of effector T cells, the cancer-intrinsic lactate signature has not been identified, and the immunotherapeutic efficacy and potential mechanism of the lactate signature are still unclear. Methods: We defined a pan-cancer up-lactate score by comparing malignant tissues and normal tissues in the TCGA cohort. The immunotherapeutic efficacy was evaluated in non-small cell lung cancer (NSCLC), metastatic renal cancer (mRCC), bladder cancer (BLCA) and melanoma cohorts. The cancer cell-intrinsic mechanism to immune checkpoint inhibitors (ICIs) resistance was measured using single cell sequencing (scRNA-seq) data. Pathway activation was evaluated in the TCGA cohort and CPTAC cohort with transcriptomics and proteomics. The co-occurrence of up-lactate signature and mTOR signaling was determined by spatial transcriptomics of the tissue samples. Immunotherapy resistance and pathway regulation were validated in the in-house NSCLC cohort. Results: Patients with the high up-lactate scores had significantly short overall survival (OS) than those with the low up-lactate scores (p < 0.001) across multiple types of cancers. The up-regulated lactate signature exhibited higher expression in the malignant cells compared with stromal cells and immune cells in multiple scRNA-seq datasets. A high up-lactate score was associated with poor OS in NSCLC, mRCC, BLCA and melanoma patients who received anti-PD(L)1 antibody. The up-lactate score was higher in the responders of cancer cells, but not in immune cells and stromal cells compared with the non-responders (p < 0.05). Moreover, up-lactate score was positively correlated with mTOR signaling across multiple cancers. In patients with NSCLC who received anti-PD-1 antibody, higher up-lactate scores were associated with significantly shorter PFS compared to lower up-lactate scores (p < 0.001). Additionally, the up-lactate score was associated with cold tumor, and was positively correlated with mTOR signaling. Conclusion: Collectively, we defined a pan-cancer up-lactate signature, which is a feature of malignant cells and is associated with ICIs resistance. This reveals a coherent program with prognostic and predictive value that may be therapeutically targeted.http://www.sciencedirect.com/science/article/pii/S2405844024155223LactateImmunosuppressionImmune checkpoint inhibitorCancer intrinsic feature |
| spellingShingle | Shuiting Fu Jiachen Xu Chunming Wang Cheng Zhang Chengcheng Li Wenchuan Xie Guoqiang Wang Xin Zhu Yuyan Xu Yaohong Wen Jingyuan Pei Jun Yang Mingyang Tang Hongkun Tan Shangli Cai Lei Cai Mingxin Pan Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis Heliyon Lactate Immunosuppression Immune checkpoint inhibitor Cancer intrinsic feature |
| title | Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis |
| title_full | Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis |
| title_fullStr | Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis |
| title_full_unstemmed | Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis |
| title_short | Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis |
| title_sort | cancer specific up regulated lactate genes associated with immunotherapy resistance in a pan cancer analysis |
| topic | Lactate Immunosuppression Immune checkpoint inhibitor Cancer intrinsic feature |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024155223 |
| work_keys_str_mv | AT shuitingfu cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT jiachenxu cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT chunmingwang cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT chengzhang cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT chengchengli cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT wenchuanxie cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT guoqiangwang cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT xinzhu cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT yuyanxu cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT yaohongwen cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT jingyuanpei cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT junyang cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT mingyangtang cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT hongkuntan cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT shanglicai cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT leicai cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis AT mingxinpan cancerspecificupregulatedlactategenesassociatedwithimmunotherapyresistanceinapancanceranalysis |