IP-score correlated to endogenous tumour antigen peptide processing: A candidate clinical response score algorithm of immune checkpoint inhibitors therapy in multiple cohorts

Abstract

The processing of endogenous tumour antigen peptides was essential for anti-tumour immunity in the tumour microenvironment. A high degree of Endogenous tumour antigen peptide processing has been demonstrated to improve the prognosis of carcinoma patients. However, there is insufficient evidence to prove its effect on the clinical response to immune checkpoint inhibitor therapy. To undertake a more in-depth analysis of the effects of the aforementioned genes on immunotherapy, we constructed a gene set evaluation score system relevant to tumour endogenous antigen peptide therapy using the GSVA approach. This rating mechanism is known as IP score (IPs). Immediately afterwards, we used the TCGA pan-cancer cohorts to conduct a comprehensive analysis of 6 genes in the IPs, and the analysis results showed that these six genes were related to the proportion of CD8+ T lymphocytes in a variety of solid tumours. As a prognostic protective factor for solid tumours, patients had better prognosis outcomes in the group with high expression levels of the above genes. We analysed the differential expression of six genes between immune checkpoint inhibitor treatment response and disease progression groups using several treatment cohorts. The results revealed that after treatment with PD-1 or CTLA4 inhibitors, the expression levels of the above six genes were comparatively high in the effective group, but the expression of the signature genes was dramatically downregulated in the ICI-insensitive groups. This indicates that the 6 genes are related to the clinical response to ICI treatment. Finally, we used the GSVA method to evaluate the above signatures, and the results showed that PDCD1, CTAL4, CD274 and LAG3 were significantly higher expressed in the IPs high-expression group; therefore, based on the processing of endogenous antigenic peptides in tumours, a predictive score of clinical response to immune checkpoint inhibitor therapy composed of 6 genes(PSMB8/PSMB9/PSMB10/PSME1/PSME2/IRF1) was constructed, and the role of each independent variable in the signature in the solid tumour microenvironment and the impact on ICI treatment were comprehensively analysed. This study provides a candidate evaluation score for predicting clinical response to immune checkpoint inhibitor therapy.