Leveraging diverse cell-death related signature predicts the prognosis and immunotherapy response in renal clear cell carcinoma

Background: Modulation of programmed cell death in tumor cells alters the tumor microenvironment and the influx of tumor-infiltrating lymphocytes, and the combination of its inducers and immune checkpoint inhibitors plays a synergistic role in enhancing antitumor effects.

Methods: We downloaded the data of clear cell renal cell carcinoma samples from The Cancer Genome Atlas and used a machine learning approach to build a new programmed cell death index (PCDI) through 13 programmed cell death-related genes. Based on PCDI, clinical features, tumor immune microenvironment, chemotherapy response and immunotherapy response were systematically analyzed.

Results: PCDI consists of eight programmed cell death-related genes (TBX3, BID, TCIRG1, IDUA, KDR, PYCARD, IFNG and LRRK2). PCDI is a reliable predictor of survival in clear cell renal cell carcinoma patients and has been validated in multiple external datasets. We found that the high PCDI group showed higher levels of immune cell infiltration and better response to immunotherapy compared to the low PCDI group, and PCDI can also be used for prognostic prediction in a variety of cancers other than clear cell renal cell carcinoma. In vitro experiments demonstrated that knockdown of IDUA inhibited the proliferation and migration of clear cell renal cell carcinoma.

Conclusions: The PCDI identified in this study provides valuable insights into the clinical management of clear cell renal cell carcinoma by accurately evaluating the prognosis of patients with clear cell renal carcinoma and identifying the patient population that would benefit from immunotherapy.