title: Programmed death 1 blockade, an Achilles heel for MMR-deficient tumors?
abstract: Program death receptor-1 (PD-1) is upregulated in many tumors and in tumor microenvironment, and PD-1 blockade has led to remarkable immune-based anti-tumor responses in across many tumor types. Pembrolizumab, an anti-programmed death 1 checkpoint inhibitor, resulted in a high rate of immune response in 41 patients with previously treated mismatch repair (MMR)-deficient tumor including colorectal cancer but not in MMR-stable tumor with expectant toxicities. Both immune-based progression-free and overall survival are quite promising and correlate with high mutation loads in the tumor. MMR-deficient tumors made up not an insignificant proportion of GI and GU cancers and are found mostly in younger patients who had better prognosis than MMR-stable tumors. However, MMR-deficient tumors do not respond to cytotoxic chemotherapy as these agents may require intact DNA mismatch repair to be effective. MMR deficiency occurred as a result of mutations in defined DNA repair complex mutations or epigenetics modifications and gene upstream of DNA repair complex. PD-1 blockade represents our first successful shot at one of the Achilles heels of this MMR-deficient tumor Goliath. Only coordinated attack on all of its Achilles heels and healing mechanisms can this tumor Goliath be brought down to its knees.
authors.affiliation: SIR RUN RUN SHAW Hospital, School of Medicine, Zhe-Jiang University, Hangzhou, China. yingjielin1984@163.com.
authors.forename: Andy Yingjie
authors.initials: AY
authors.lastname: Lin
authors.affiliation: P4 Medicine Institute, Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, University of Washington Medical Center, Seattle, WA, 98109, USA. elin@p4mi.org.
authors.forename: Edward
authors.initials: E
authors.lastname: Lin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053843:DNA Mismatch Repair / Q000235:genetics*; D006801:Humans; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab; D000070957:MutL Protein Homolog 1