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.

Over-activated PD-1/PD-L1 axis facilitates the chemoresistance of diffuse large B-cell lymphoma cells to the CHOP regimen

“…As an immune checkpoint, PD-1 serves an important role in downregulating the immune system by preventing the activation of T cells (12). It was demonstrated that the inhibitory effect of PD-1 is accomplished through a mechanism of promoting apoptosis (12).…”

“…As an immune checkpoint, PD-1 serves an important role in downregulating the immune system by preventing the activation of T cells (12). It was demonstrated that the inhibitory effect of PD-1 is accomplished through a mechanism of promoting apoptosis (12). The present study applied rPD-1 (7.5 µg/ml) on CHOP-treated CRL2631 cells, and it was identified that CHOP-induced reduction of cell survival was significantly prevented by rPD-1 pre-treatment (Fig.…”

“…The ratio of the four drugs was 80 mg/5.5 mg/0.16 mg/11.1 mg (9-11). For PD-1 stimulation, cells were exposed to 7.5 µg/ml recombinant human PD-1 (rPD-1; R&D Systems, Inc., Minneapolis, MN, USA) in serum-free GlutaMAX™ RPMI-1640 medium (Invitrogen; Thermo Fisher Scientific, Inc.) for 24 h prior to CHOP treatment (12). To block PI3K/Akt1 signaling, the selective PI3K inhibitor (iPI3K) BKM120 (cat no.…”

T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts

“…Sustained inhibitory signaling mediated by expression of numerous co-signaling molecules on T cells such as TIM-3, LAG-3, PD-1 or CTLA-4 correlates with a stage of T-cell exhaustion, marked by a reduced T-cell effector function, proliferative potential and cytotoxicity [13, 14]. Since T-cell function is essential for tumor control [15, 16], efforts are made to increase T-cell function and to reverse T-cell exhaustion for induction of a sustained tumor immune surveillance and efficient elimination of malignant cells [17]. Recent advances were achieved by targeting immune escape checkpoints such as CTLA-4 or PD-1 [13, 18, 19].…”

Single nucleotide polymorphisms of casitas B-lineage lymphoma proto-oncogene-b predict outcomes of patients with advanced non-small cell lung cancer after first-line platinum based doublet chemotherapy

“…And inhibition of PD-1/ PD-L1 by anti-PD-1 antibody strengthen doxorubicin NSCLC, non-small cell lung cancer; NLR, neutrophil-to-lymphocyte ration; PLR, platelet-to-lymphocyte ratio; PFS, progression free survival; OS, overall survival; CI, confidence interval; HR, hazards ratio. to inhibit metastasis in vivo (40). According to the above evidences, immunotherapy targeting the immune response modulating genes might have synergistic effect with chemotherapy to eliminate tumor cells.…”