Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis.

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.

Oncotarget. 2016 Feb 07 [Epub ahead of print]

Madison Black, Ivraym B Barsoum, Peter Truesdell, Tiziana Cotechini, Shannyn K Macdonald-Goodfellow, Margaret Petroff, D Robert Siemens, Madhuri Koti, Andrew W B Craig, Charles H Graham

Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. , Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. , Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. , Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. , Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. , Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA. , Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. , Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. , Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. , Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.

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