Construction and Validation of a Novel Immune Checkpoint-Related Model in Clear Cell Renal Cell Carcinoma

Abstract

Background. With the highest mortality and metastasis rate, kidney renal clear cell carcinoma (KIRC) is one of the most common urological malignant tumors and not sensitive to chemotherapy and radiotherapy. Immunotherapy, which proves to be effective and a big progression, such as PD-1/PD-L1 inhibitors, is not sensitive to all KIRC patients. To predict prognosis and immunotherapy response, a novel immune checkpoint gene- (ICG-) related model is essential in clinics. Methods. From the public database-downloaded dataset, a novel ICG-related model for predicting prognosis and immunotherapy response in KIRC patients was built up and verified with R packages and Cox regression analysis. The Kaplan-Meier curve was plotted. Results. 39 ICGs were identified to have different expression in KIRC patients and enriched in immune-related biological pathways and activities. Three ICGs (CTLA4, TNFSF14, and HHLA2) were screened to generate KIRC-ICG model. The KIRC-ICG model was verified to be effective. With conducting KIRC-SYS model, KIRC-ICGscore was verified to be an independent factor regardless of age, gender, stage, grade, and TNM stage. Compared to the ICG-low subgroup, the ICG-high subgroup had more immune activities. KIRC-ICGscore was significantly positively correlated with the expression of Treg markers. KIRC-ICG model could also be reliable to predict immunotherapy response. Conclusion. The KIRC-ICG model was reliable to predict prognosis and immunotherapy response for KIRC patients and could be an independent factor regardless of clinical characteristics.

The Importance of HHLA2 in Solid Tumors—A Review of the Literature

“…The high-risk subgroup presented a higher TIDE score, meaning a worse response to immunotherapy. These results may also implicate the connection of the risk score-and lowered HHLA2 expression-with immunosuppressive responses [77].…”

“…Several studies indicated unfavorable clinical outcomes associated with the overexpression of HHLA2. However, multiple reports have identified HHLA2 as a protective factor [19,33,35,36,77]. Altogether, the number of studies tackling the issue of the role and expression of HHLA2 in different types of malignancies is poor, which results in contradictory conclusions.…”

Expression, Prognostic and Immunological Roles of USP8 in kidney renal clear cell carcinoma: An Integrated Analysis

“…Subsequently, KEGG pathway enrichment analyses was applied and the results suggested that USP8 was mainly enriched in immune and metabolic processes, including ErbB signaling pathway, Ubiquitin mediated proteolysis, EGFR tyrosine kinase inhibitor resistance as well as PD-L1 expression and PD-1 checkpoint pathway in cancer. Emerging studies demonstrated that these pathway were signi cantly related to the occurrence, prognosis, and metastasis of KIRC [46-48] and PD-L1 expression and PD-1 checkpoint pathway [49] may be a molecular target and potential therapeutic strategy for USP8 in KIRC. Several research reported the underlying crosstalk between ErbB signaling pathway, Ubiquitin mediated proteolysis, EGFR tyrosine kinase inhibitor resistance, etc.…”