Identification of subtypes correlated with tumor immunity and immunotherapy in cutaneous melanoma

Qian Liu; Rongfang Nie; Mengyuan Li; Lin Li; Haiying Zhou; Hui Lu; Xiaosheng Wang

doi:10.1016/j.csbj.2021.08.005

Identification of subtypes correlated with tumor immunity and immunotherapy in cutaneous melanoma

Comput Struct Biotechnol J. 2021 Aug 6:19:4472-4485. doi: 10.1016/j.csbj.2021.08.005. eCollection 2021.

Authors

Qian Liu^{1

2

3}, Rongfang Nie^{1

2

3}, Mengyuan Li^{1

2

3}, Lin Li^{1

2

3}, Haiying Zhou⁴, Hui Lu⁴, Xiaosheng Wang^{1

2

3}

Affiliations

¹ Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
² Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
³ Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China.
⁴ Department of Orthopedics, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.

Abstract

Because immune checkpoint inhibitors (ICIs) are effective for a subset of melanoma patients, identification of melanoma subtypes responsive to ICIs is crucial. We performed clustering analyses to identify immune subtypes of melanoma based on the enrichment levels of 28 immune cells using transcriptome datasets for six melanoma cohorts, including four cohorts not treated with ICIs and two cohorts treated with ICIs. We identified three immune subtypes (Im-H, Im-M, and Im-L), reproducible in these cohorts. Im-H displayed strong immune signatures, low stemness and proliferation potential, genomic stability, high immunotherapy response rate, and favorable prognosis. Im-L showed weak immune signatures, high stemness and proliferation potential, genomic instability, low immunotherapy response rate, and unfavorable prognosis. The pathways highly enriched in Im-H included immune, MAPK, apoptosis, calcium, VEGF, cell adhesion molecules, focal adhesion, gap junction, and PPAR. The pathways highly enriched in Im-L included Hippo, cell cycle, and ErbB. Copy number alterations correlated inversely with immune signatures in melanoma, while tumor mutation burden showed no significant correlation. The molecular features correlated with favorable immunotherapy response included immune-promoting signatures and pathways of PPAR, MAPK, VEGF, calcium, and glycolysis/gluconeogenesis. Our data recapture the immunological heterogeneity in melanoma and provide clinical implications for the immunotherapy of melanoma.

Keywords: Clustering analysis; DMFS, distant-metastasis free survival; DSS, disease-specific survival; EMT, epithelial-mesenchymal transition; FDR, false discovery rate; GO, gene ontology; GSEA, gene-set enrichment analysis; HLA, human leukocyte antigen; HRD, homologous recombination deficiency; ICIs, immune checkpoint inhibitors; Immune subtypes; Immunotherapy; MDSC, myeloid-derived suppressor cell; Melanoma; NK, natural killer; OS, overall survival; SCNAs, somatic copy number alterations; TCGA, The Cancer Genome Atlas; TIME, tumor immune microenvironment; TMB, tumor mutation burden; TME, tumor microenvironment; Tumor immune microenvironment; WGCNA, weighted gene co-expression network analysis; ssGSEA, single-sample gene-set enrichment analysis.