Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells.
Although small cell lung cancer (SCLC) is highly responsive to chemotherapies (e.g., cisplatin-etoposide doublet), virtually almost all responsive SCLC patients experience disease recurrence characterized by drug resistance. The mechanisms underlying cisplatin resistance remain elusive. Here we report that cell-intrinsic expression of PD1 and PD-L1, two immune checkpoints, is required for sustained expansion of SCLC cells under cisplatin selection. Indeed, PD1 and PD-L1 were expressed at a higher level in lung cancer cell lines, tumor tissues, and importantly, in SCLC cells resistant to cisplatin (H69R, H82R), when compared to respective controls. Genetic abrogation of PD1 and PD-L1 in H69R and H82R cells decreased their proliferation rate, and restored their sensitivity to cisplatin. Mechanistically, PD-L1 upregulation in H69R and H82R cells was attributed to the overexpression of DNA methyltransferase 1 (DNMT1) or receptor tyrosine kinase KIT, as knockdown of DNMT1 or KIT in H69R and H82R cells led to PD-L1 downregulation. Consequently, combined knockdown of PD-L1 with KIT or DNMT1 resulted in more pronounced inhibition of H69R and H82R cell growth. Thus, cell intrinsic PD1/PD-L1 signaling may be a predictor for poor efficacy of cisplatin treatment, and targeting the cellular PD1/PD-L1 axis may improve chemosensitization of aggressive SCLC.
The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, Minnesota, 55912, United States of America.
Fei
F
Yan
The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, Minnesota, 55912, United States of America.
Jiuxia
J
Pang
Department of Thoracic Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University /Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Yong
Y
Peng
Department of Medical Oncology, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota, 55905, United States of America.
Julian R
JR
Molina
Division of Epidemiology, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota, 55905, United States of America.
Ping
P
Yang
The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, Minnesota, 55912, United States of America.
Shujun
S
Liu
D060890:B7-H1 Antigen / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055752:Small Cell Lung Carcinoma / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects
D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D019009:Proto-Oncogene Proteins c-kit; D002945:Cisplatin