Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment.
PD-1/PD-L1 blockade appears to be a very promising immunotherapy with significant clinical benefits and durable responses in multiple tumor types. However, the effectual clinical benefits of PD-1/PD-L1 blockade are hampered by a high rate of primary resistance, where patients do not respond to PD-1/PD-L1 blockade initially. And more distressingly, most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms underlying primary and acquired resistance to PD-1/PD-L1 blockade have remained ambiguous. This review documents in detail the current understanding of the mechanisms through which resistance to anti-PD1/PD-L1 therapy occurs. The mechanisms underlying primary resistance to PD-1/PD-L1 blockade contain several immunoregulatory factors affecting tumor-specific immune responses within the immune microenvironment, co-enrichment of a group of 26 transcriptomic signatures (named innate anti-PD-1 resistance (IPRES) signatures) and cancer-cell-autonomous cues. The mechanism attributable to acquired resistance harbors evolution of neoantigen landscape, mutations of JAK and β-2-microglobulin, and epigenetic stability of exhausted T cells. At last, the promising therapeutic strategies to sensitize the resistant patients are also briefly discussed.
Department of Obstetrics & Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China.
Qiaohong
Q
Wang
Department of Obstetrics & Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China. Electronic address: wuxia1225@aliyun.com.
Xia
X
Wu
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000276:immunology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D006801:Humans; D000068884:Immunosenescence; D007167:Immunotherapy / Q000379:methods*; D053612:Janus Kinases / Q000235:genetics; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000502:physiology*; D059467:Transcriptome; D059016:Tumor Microenvironment / Q000187:drug effects
D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D061026:Programmed Cell Death 1 Receptor; D053612:Janus Kinases
Acquired resistance; Checkpoint inhibitors; PD-1; PD-L1; Primary resistance