Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells

Abstract

The clinical success of immunotherapy that inhibits the negative immune regulatory pathway programmed cell death protein 1/PD-1 ligand (PD-1/PD-L1) has initiated a new era in the treatment of metastatic cancer. PD-L1 expression is upregulated in many solid tumors including lung cancer and functions predominantly in lactate-enriched tumor microenvironments. Here, we provided evidence for PD-L1 induction in response to lactate stimulation in lung cancer cells. Lactate-induced PD-L1 induction was mediated by its receptor GPR81. The silencing of GPR81 signaling in lung cancer cells resulted in a decrease in PD-L1 protein levels and functional inactivation of PD-L1 promoter activity. In addition, GPR81-mediated upregulation of PD-L1 in glucose-stimulated lung cancer cells that recapitulates the enhanced glycolysis in vivo was dependent on lactate dehydrogenase A (LDHA). We also demonstrated that activation of GPR81 decreases intracellular cAMP levels and inhibits protein kinase A (PKA) activity, leading to activation of the transcriptional coactivator TAZ. Interaction of TAZ with the transcription factor TEAD was essential for TAZ activation of PD-L1 and induction of its expression. Furthermore, we found that lactate-induced activation of PD-L1 in tumor cells led to reduced production of interferon-γ and induction of apoptosis of cocultured Jurkat T-cell leukemia cells. Our findings reveal an unexpected role of lactate in contributing to tumor cell protection from cytotoxic T-cell targeting and establishes a direct connection between tumor cell metabolic reprograming and tumor evasion from the immune response.

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

“…In the physiological context, lactate binds to GPR81, which inhibits lipolysis in fat cells (121). In the cancer context, modulation of lactate-sensing proteins, such as MCTs, ultimately leads to tumor proliferation and dissemination (122), escape from the immune system (123) and therapy resistance (124). GPR81 expression is upregulated in cervical (125), breast (126) and liver cancer (122), and associated with the progression of cervical squamous carcinoma (125).…”

“…GPR81 is highly expressed in different cancer cell lines including colon, breast, lung, hepatocellular, cervical, and pancreatic (122,126). In vitro, GPR81 expression associated with cancer cell survival, proliferation, migration, invasion and resistance to chemotherapy, and is involved in the suppression of antitumor immunity by promoting the overexpression of PD-L1 in lung cancer cells lines (123,124,126). Knockdown of GPR81 in a xenograft cancer model resulted in reduction of tumor growth and metastasis (122,126).…”

Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

“…WNT/β-catenin signaling plays a central role, not only in regulation of immune cell homeostasis, development and function, but also impacts circulating immune cells,including control of peripheral T cell activation, differentiation and tumor-immune cell interplay 19 . Active YAP signaling may support immune evasion in cancer and melanoma by inducing PD-L1 expression 28,29 ( Supplementary Fig. 18) while another report shows that enhanced YAP signaling, due to loss of LATS1/2, may promote anti-cancer immune response 30 .…”

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

“…Recently, PD‐L1 expression has been shown to be up regulated by lactate‐enriched TME in solid tumours, with a mechanism involving lactate stimulation of the receptor GPR81 in lung cancer cells that exhibit enhanced glycolysis and lactate dehydrogenase activities . GPR81 inhibits protein kinase A by decreasing cAMP so as to increase the transcriptional co‐activator TAZ that activates Pd‐l1 gene transcription, by interacting with the transcription factor TEAD, resulting in lactate‐induced activation of PD‐L1 in tumour cells with reduced IFN‐γ and apoptosis of co‐cultured Jurkat T‐cell leukaemia cells .…”

“…57 GPR81 inhibits protein kinase A by decreasing cAMP so as to increase the transcriptional co-activator TAZ that activates Pd-l1 gene transcription, by interacting with the transcription factor TEAD, resulting in lactate-induced activation of PD-L1 in tumour cells with reduced IFN-γ and apoptosis of co-cultured Jurkat T-cell leukaemia cells. 32,57 Contrasting to lung cancer cells where TEAD and TAZ that interact with Pd-l1 promoter under the conditions of PARP-1 is an enzyme that uses NAD+ as a co-enzyme to catalyse protein post-translational modification with poly(ADP-ribose) chains that are attached to PARP-1 itself or its substrate proteins. Inhibiting PARPs has been demonstrated to be an effective therapeutic strategy to tumours associated with germline mutation in double-strand DNA repair genes.…”