title: Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis.
abstract: The ability of tumor cells to avoid immune destruction (immune escape) as well as their acquired resistance to anti-cancer drugs constitute important barriers to the successful management of cancer. Interaction between the Programmed Death Ligand 1 (PD-L1) on the surface of tumor cells with the Programmed Death-1 (PD-1) receptor on cytotoxic T lymphocytes leads to inactivation of these immune effectors and, consequently, immune escape. Here we show that the PD-1/PD-L1 axis also leads to tumor cell resistance to conventional chemotherapeutic agents. Using a panel of PD-L1-expressing human and mouse breast and prostate cancer cell lines, we found that incubation of breast and prostate cancer cells in the presence of purified recombinant PD-1 resulted in resistance to doxorubicin and docetaxel as determined using clonogenic survival assays. Co-culture with PD-1-expressing Jurkat T cells also promoted chemoresistance and this was prevented by antibody blockade of either PD-L1 or PD-1 or by silencing of the PD-L1 gene. Moreover, inhibition of the PD-1/PD-L1 axis using anti-PD-1 antibody enhanced doxorubicin chemotherapy to inhibit metastasis in a syngeneic mammary orthotopic mouse model of metastatic breast cancer. To further investigate the mechanism of tumor cell survival advantage upon PD-L1 ligation, we show that exposure to rPD-1 promoted ERK and mTOR growth and survival pathways leading to increased cell proliferation. Overall, the findings of this study indicate that combinations of chemotherapy and immune checkpoint blockade may limit chemoresistance and progression to metastatic disease.
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
authors: Madison
authors: M
authors: Black
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.|Department of Urology, Queen's University, Kingston, Ontario, Canada.
authors: Ivraym B
authors: IB
authors: Barsoum
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.|Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada.
authors: Peter
authors: P
authors: Truesdell
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
authors: Tiziana
authors: T
authors: Cotechini
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
authors: Shannyn K
authors: SK
authors: Macdonald-Goodfellow
authors: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA.
authors: Margaret
authors: M
authors: Petroff
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.|Department of Urology, Queen's University, Kingston, Ontario, Canada.
authors: D Robert
authors: DR
authors: Siemens
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.|Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada.
authors: Madhuri
authors: M
authors: Koti
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.|Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada.
authors: Andrew W B
authors: AW
authors: Craig
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.|Department of Urology, Queen's University, Kingston, Ontario, Canada.|Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario, Canada.
authors: Charles H
authors: CH
authors: Graham
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D018920:Coculture Techniques; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D043823:Taxoids / Q000494:pharmacology*; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin
keywords: PD-1; PD-L1; chemoresistance; immune escape; metastasis