Biological Pathway-Derived TMB Robustly Predicts the Outcome of Immune Checkpoint Blockade Therapy

Ya-Ru Miao; Chun-Jie Liu; Hui Hu; Mei Yang; An-Yuan Guo

doi:10.3390/cells11182802

Biological Pathway-Derived TMB Robustly Predicts the Outcome of Immune Checkpoint Blockade Therapy

Cells. 2022 Sep 8;11(18):2802. doi: 10.3390/cells11182802.

Authors

Ya-Ru Miao¹, Chun-Jie Liu¹, Hui Hu¹, Mei Yang¹, An-Yuan Guo^{1

2}

Affiliations

¹ Center for Artificial Intelligence Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
² Research Institute of Huazhong University of Science and Technology in Shenzhen, Shenzhen 518000, China.

Abstract

Although immune checkpoint blockade (ICB) therapies have achieved great progress, the patient response varies among cancers. In this study, we analyzed the potential genomic indicators contributing to ICB therapy response. The results showed that high tumor mutation burden (TMB) failed to predict response in anti-PD1 treated melanoma. SERPINB3 was the most significant response-related gene in melanoma and mutations in either SERPINB3 or PEG3 can serve as an independent risk factor in melanoma. Some recurrent mutations in CSMD3 were only in responders or non-responders, indicating their diverse impacts on patient response. Enrichment scores (ES) of gene mutations in 12 biological pathways were significantly higher in responders or non-responders. Next, the P-TMB calculated from genes in these pathways was significantly related to patient response with prediction AUC 0.74-0.82 in all collected datasets. In conclusion, our work provides new insights into the application of TMB in predicting patient response, which will benefit to immunotherapy research.

Keywords: SERPINB3; TMB; immunotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Immunotherapy / methods
Melanoma* / drug therapy
Melanoma* / genetics
Melanoma* / pathology
Mutation / genetics

Substances

Biomarkers, Tumor
Immune Checkpoint Inhibitors

Grants and funding

This research was funded by Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20210324141814037) and the National Natural Science Foundation of China (Grant Nos. 31822030 and 31771458).