The interaction between the Programmed Death Ligand 1 (PD-L1) immune checkpoint on the tumor cell surface with the Programmed Death-1 (PD-1) receptor on cytotoxic T lymphocytes (CTLs) leads to CTL inactivation, thereby promoting tumor cell escape from adaptive immunity. We previously demonstrated that signaling by PD-L1/PD-1 is bidirectional and leads to activation of oncogenic pathways as well as drug resistance in tumor cells. We also have preliminary evidence that Immunity Related GTPase M, an important mediator of autophagy, is up-regulated by PD-1/PD-L1 reverse signaling. Autophagy is a well-established mechanism of drug resistance in cancer cells. This led us to hypothesize that PD-1/PD-L1 signaling induces drug resistance in tumor cells by up-regulating autophagy. The MEK/ERK and the PI3K/Akt signaling pathways are known to increase and decrease autophagy, respectively. Breast cancer cells exposed to rPD-1 showed a time dependent increase in extracellular signal–regulated kinase (ERK) activation and a decrease in protein kinase B (Akt) activation. Conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II is a requirement for autophagosome formation and is a robust marker of autophagy. Exposure of human breast cancer cells to recombinant PD-1 (rPD-1) showed a time-dependent increase in LC-3 II. We are currently conducting additional studies to confirm that the activation of PD-L1 signaling in tumor cells up-regulates autophagy. These results provide evidence that PD-1/PD-L1 reverse signaling activates autophagy as a potential mechanism of cancer cell chemoresistance. (Supported by a grant from the Canadian Institutes of Health Research.) Citation Format: Lori M. Minassian, Shannyn K. MacDonald-Goodfellow, Peter Truesdell, Daniel Sanwalka, Andrew W. Craig, Madhuri Koti, D Robert Siemens, Charles H. Graham. Tumor cell drug resistance induced by the programmed death ligand 1 (PD-L1) immune checkpoint is associated with autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3960. doi:10.1158/1538-7445.AM2017-3960
Background: While the Programmed Death 1/Programmed Death Ligand 1 (PD-1/PD-L1) immune checkpoint is an important mechanism of immune evasion in cancer, recent studies have shown that it can also lead to resistance to chemotherapy in cancer cells via reverse signaling. Here we describe a novel mechanism by which autophagy mediates cancer cell drug resistance induced by PD-1/PD-L1 signaling. Methods: Human and mouse breast cancer cells were treated with recombinant PD-1 (rPD-1) to stimulate PD-1/PD-L1 signaling. Activation of autophagy was assessed by immunoblot analysis of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II and Beclin 1 protein levels, two important markers of autophagy. Moreover, autophagosome formation was assessed in human breast cancer cells using green fluorescence protein (GFP)-tagged LC3. Cells were either treated with Beclin 1 or Atg7 shRNA to assess the role of autophagy on resistance to doxorubicin mediated by PD-1/PD-L1 signalling. We then investigated signaling mechanisms upstream of PD-1/PD-L1 induced autophagy by assessing phosphorylation of extracellular signal-related kinase (ERK). Results: Treatment of cells with rPD-1 resulted in a time-dependent increase in LC3-II as well as Beclin 1, and an increase in autophagosome formation. Knockdown of Beclin 1 or Atg7 prevented drug resistance induced by PD-1/PD-L1 signaling. Exposure of breast cancer cells to rPD-1 resulted in increased ERK phosphorylation and inhibition of ERK activation abolished autophagy induced by PD-1/PD-L1 signaling. Conclusions: These studies provide a rationale for the use of PD-1/PD-L1 immune checkpoint blockers and autophagy inhibitors as potential chemosensitizers in cancer therapy.
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