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Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis
Shuiting Fu1, Jiachen Xu2,3, Chunming Wang4
1Department 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, 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.
