Abstract
A large proportion of anti-tumor immunity research is focused on major histocompatibility complex class I (MHC-I) molecules and CD8+ T cells. Despite mounting evidence has shown that CD4+ T cells play a major role in anti-tumor immunity, the role of the MHC-II molecules in tumor immunotherapy has not been thoroughly researched and reported. In this study, we defined a MHC-II signature for the first time by calculating the enrichment score of MHC-II protein binding pathway with a single sample gene set enrichment analysis (ssGSEA) algorithm. To evaluate and validate the predictive value of the MHC class II (MHC-II) signature, we collected the transcriptome, mutation data and matched clinical data of bladder cancer patients from IMvigor210, The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) databases. Comprehensive analyses of immunome, transcriptome, metabolome, genome and drugome were performed in order to determine the association of MHC-II signature and tumor immunotherapy. We identified that MHC-II signature is an independent and favorable predictor of immune response and the prognosis of bladder cancer treated with immune checkpoint inhibitors (ICIs), one that may be superior to tumor mutation burden. MHC-II signature was significantly associated with increased immune cell infiltration and levels of immune-related gene expression signatures. Additionally, transcriptomic analysis showed immune activation in the high-MHC-II signature subgroup, whereas it showed fatty acid metabolism and glucuronidation in the low-MHC-II signature subgroup. Moreover, exploration of corresponding genomic profiles highlighted the significance of tumor protein p53 (TP53) and fibroblast growth factor receptor 3 (FGFR3) alterations. Our results also allowed for the identification of candidate compounds for combined immunotherapy treatment that may be beneficial for patients with bladder cancer and a high MHC-II signature. In conclusion, this study provides a new perspective on MHC-II signature, as an independent and favorable predictor of immune response and prognosis of bladder cancer treated with ICIs.
Highlights
Immune checkpoint inhibitors (ICIs) have revolutionized bladder cancer (BC) treatment options (Antoni et al, 2017)
The results showed that only MHC class II (MHC-II) signature was an independent and protective factor in the efficacy of ICIs (Figures 1B,C)
Based on the fact that enhanced tumor immunogenicity predicts improved response to ICIs, we compared the tumor mutation burden (TMB) and tumor neoantigen burden (TNB) levels between high MHC-II signature score (MHC-H) and low MHC-II signature score (MHC-L) tumors. In both the ICIcohort and the TCGA-BLCA cohort, there was no significant relationship between MHC-II signature and TMB or TNB (Figures 3C–F)
Summary
Immune checkpoint inhibitors (ICIs) have revolutionized bladder cancer (BC) treatment options (Antoni et al, 2017). A series of microRNAs (including miR-608 (Liang et al, 2017), miR-193a-3p (Deng et al, 2014), and miR-138-5p (Yang et al, 2016)) have been demonstrated serve promising biomarkers for the prognosis and drug treatment response in BC. A recent study in BC patients found that tumor response to PD-L1 blockade could be enhanced by blocking transforming growth factor β (TGFβ) with stable and reliable results (Mariathasan et al, 2018), suggesting that the use of gene signatures over single biomarkers may be more accurate in predicting the efficacy of immunotherapy
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