PD-L1 regulation in colorectal cancer and role of DNA damage induced by chemotherapies

For patients with metastatic colorectal cancer (CRC), first-line therapy is based on chemotherapeutic agents, such as oxaliplatin, 5-fluorouracil and irinotecan. These drugs increase the overall survival, but resistance to therapy appears in almost 90% of patients, and the 5-year survival rate for patients with metastatic CRC is only about 12%. During the last few years, immune checkpoints blockade therapies have been developed and show good response in different cancers, including CRC with microsatellite instability (MSI). In this CRC subtype, the response rate to anti-PD-(L)1 antibodies is high thanks to the presence of neoantigens and tumor-infiltrating lymphocytes that are associated with the anti-tumor immune response. Nivolumab and pembrolizumab, two anti-PD-1 antibodies, have been approved for CRC MSI treatment. Moreover, it has been shown that the combination of chemotherapy and anti-PD-(L)1 molecules may convert cold tumors into hot tumors in which the immune system and T-cell infiltration are activated. In addition, recent studies found that DNA damage induces PD-L1 expression. ATM, ATR, DNA-PKcs and Chk1 are key sensors of the DNA damage response that regulate PD-L1 expression. This review summarizes the current knowledge on PD-L1 regulation at the genetic, epigenetic, transcriptional and translational levels. It also describes PD-L1 activation in response to chemotherapy and DNA damage. Then, it summarizes the current clinical trials that assess anti-PD-(L)1 therapies in combination with kinase inhibitors or chemotherapeutic agents in CRC.