The efficacy of PD-1/PD-L1 blockade in cold cancers and future perspectives

• Published in: Clinical immunology (Orlando, Fla.) Vol. 226; p. 108707
• Main Authors: Majidpoor, Jamal, Mortezaee, Keywan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-05-2021
• Subjects: Cytotoxic T lymphocyte associated antigen-4 (CTLA-4); Immune checkpoint inhibitor (ICI); Microsatellite instability (MSI); Mismatch repair; Programmed death ligand 1 (PD-L1); Programmed death-1 receptor (PD-1); Treatment-related adverse events (TRAEs); Tumor microenvironment (TME); Tumor microenvironment (TME); Treatment-related adverse events (TRAEs); Cytotoxic T lymphocyte associated antigen-4 (CTLA-4); Mismatch repair; Immune checkpoint inhibitor (ICI); Programmed death-1 receptor (PD-1); Microsatellite instability (MSI); Programmed death ligand 1 (PD-L1)
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2021.108707

Colorectal cancer (CRC), and breast, ovarian, pancreatic and prostate cancers are generally considered as low immune-reactive cancers that represent either limited infiltration of immune cells or extensive infiltration of immunosuppressive T cells. Interaction between programmed death ligand 1 (PD-L1) with programmed death-1 receptor (PD-1) is important for immune evasion. Tumors positive for PD-L1 generally show higher responses to the immune checkpoint inhibition (ICI); however, the high presence of PD-L1 in a tumor is a predictor of poor prognosis. Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but responses to the ICI is meaningful. It seems that in a tumor both the PD-L1 expression and TIL infiltration is required for improving responses to the anti-PD-1/PD-L1 immunotherapy. Combination of anti-PD-1/PD-L1 with immune modulatory drugs, such as C-X-C chemokine receptor type 4 (CXCR4), poly (ADP-ribose) polymerase (PARP) or transforming growth factor (TGF)-β inhibitors has shown meaningful clinical benefits.
•Anti-PD-1/PD-L1 drugs can be used safely in patients with cold cancers.•Previous therapy lines, PD-L1 expression status, TMB and the TIL fraction affect responses to the ICI.•Responses to ICI are generally higher in PD-L1+ cancers, the high PD-L1 presence, however, is a poor prognostic marker.•Anti-PD-1/PD-L1 acts in the late phase of T cell development, namely T cell expansion and maintenance.•Anti-CTLA-4 acts in the initial phase, namely priming phase.•Anti-PD-1/PD-L1 can be used appropriately in combination with anti-CTLA-4•CXCR4, PARP or TGF-β inhibitors can be used as immune modulatory agents.