Hedgehog signaling regulates PDL-1 expression in cancer cells to induce anti-tumor activity by activated lymphocytes

Onishi, Hideya; Fujimura, Akiko; Oyama, Yoshie; Yamasaki, Akio; Imaizumi, Akira; Kawamoto, Makoto; Umebayashi, Masayo; Morisaki, T.

doi:10.1016/j.cellimm.2016.08.003

Cited by 27 publications

(22 citation statements)

References 17 publications

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“…Our data show that Hh signaling plays a role in mediating PD-L1 expression during gastric cancer development. In support of our findings, studies in pancreatic ductal adenocarcinoma cell lines revealed that Hh signaling induced PD-L1 expression under hypoxic conditions [15]. Evidence in the literature also demonstrates that the induction of PD-L1 is largely mediated by proinflammatory cytokines, of which IFNγ is the most potent [22].…”

Section: Discussionsupporting

confidence: 85%

“…Based on the TCGA data, we find that Gli2, Shh, Ptch1, Ptch2, Smo, are altered in 7%, 6%, 10%, 7% and 8% of 258 patients selected for the study, respectively [14]. Importantly, studies suggest that Hh signaling is one of regulatory pathways of PD-L1 expression and that inhibiting Hh signaling may induce lymphocyte anti-tumor activity [15]. Thus, there is interest in targeting the Hh pathway as a potential therapeutic target for the treatment of these cancers.…”

Section: Introductionmentioning

confidence: 99%

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Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer

et al. 2018

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Tumor cells expressing programmed cell death ligand 1 (PD-L1) interact with PD-1 on CD8+ cytotoxic T lymphocytes (CTLs) to inhibit CTL effector function. In gastric cancer, the mechanism regulating PD-L1 is unclear. The Hedgehog (Hh) signaling pathway is reactivated in various cancers including gastric. Here we tested the hypothesis that Hh-induced PD-L1 inactivates effector T cell function and allows gastric cancer cell proliferation. Mouse organoids were generated from tumors of a triple-transgenic mouse model engineered to express an activated GLI2 allele, GLI2A, in Lgr5-expressing stem cells, (mTGOs) or normal mouse stomachs (mGOs). Bone marrow-derived dendritic cells (DCs) were pulsed with conditioned media collected from normal (mGOCM) or cancer (mTGOCM) organoids. Pulsed DCs and CTLs were then co-cultured with either mGOs or mTGOs in the presence of PD-L1 neutralizing antibody (PD-L1Ab). Human-derived gastric cancer organoids (huTGOs) were used in drug and xenograft assays. Hh/Gli inhibitor, GANT-61 significantly reduced the expression of PD-L1 and tumor cell proliferation both in vivo and in vitro. PD-L1Ab treatment induced tumor cell apoptosis in mTGO/immune cell co-cultures. GANT-61 treatment sensitized huTGOs to standard-of-care chemotherapeutic drugs both in vivo and in vitro. Thus, Hh signaling mediates PD-L1 expression in gastric cancer cells and subsequently promotes tumor proliferation.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer

et al. 2018

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“…Thereafter, the lymphocytes were transferred and cultured in RPMI‐1640 medium for an additional 6 days. Next, we collected activated lymphocytes and used them in experiments 24 . Activated PBMCs were coincubated with H2228 cells for 48 hours at the effector : target ratio of 5:1.…”

Section: Methodsmentioning

confidence: 99%

“…Thereafter, cells were rinsed twice with PBS and incubated in PBS containing 5% BSA and 0.1% NaN 3 and the appropriate concentration of labeled mAb for 1 hour at 4°C. After washing with FACS, the fluorescence intensity or percentage of positive cells was measured using a FACSCalibur flow cytometer (FACSCanto II; BD Biosciences) and analyzed with CellQuest software (BD Biosciences) 24 …”

Section: Methodsmentioning

confidence: 99%

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In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand‐1 inhibitor in anaplastic lymphoma kinase‐rearranged non‐small‐cell lung cancer

et al. 2020

Cancer Science

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Both ceritinib (CER) and programmed cell death (PD)‐1/PD ligand‐1 (PD‐L1) have brought significant breakthroughs for anaplastic lymphoma kinase (ALK)‐rearranged non‐small‐cell lung cancer (NSCLC). However, the overall clinical efficacy of either CER or PD‐1/PD‐L1 inhibitor monotherapy has been limited to a large extent. In addition, the antitumor effect of combined CER and PD‐L1 inhibitor in ALK‐rearranged NSCLC is not fully understood. In H2228 cells, we examined the tumor killing effect of CER plus PD‐L1 inhibitor in vitro by quantitative RT‐PCR, flow cytometry, ELISA, western blot analysis, PBMC coculture system, and plasmid and transfection experiments. A Ba/F3 (EML4‐ALK‐WT) xenograft mouse model was also utilized to further evaluate the synergistic anticancer effects of CER and PD‐L1 inhibitor in vivo. The coculture system of PBMCs with H2228 cells promotes the expression of PD‐L1 and phospho‐ERK, and combined treatments facilitate lymphocyte proliferation and activation, inhibit PD‐L1 expression, and enhance lymphocyte cytotoxicity and cell death. In the in vivo NSCLC xenograft model, the volumes of tumors treated with CER and PD‐L1 inhibitor in combination were significantly smaller than those treated with CER or PD‐L1 alone. The relative tumor growth inhibitions were 84.9%, 20.0%, and 91.9% for CER, PD‐L1 inhibitor, and CER plus PD‐L1 groups, respectively. Ceritinib could synergize with PD‐1/PD‐L1 blockade to yield enhanced antitumor responses along with favorable tolerability of adverse effects. Ceritinib and PD‐L1 inhibitor combined produced a synergistic antineoplastic efficacy in vitro and in vivo, which provides a key insight and proof of principle for evaluating CER plus PD‐L1 blockade as combination therapy in clinical therapeutic practice.

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Hypoxia and pancreatic ductal adenocarcinoma

2020

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Hedgehog signaling regulates PDL-1 expression in cancer cells to induce anti-tumor activity by activated lymphocytes

Cited by 27 publications

References 17 publications

Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer

Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer

In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand‐1 inhibitor in anaplastic lymphoma kinase‐rearranged non‐small‐cell lung cancer

Hypoxia and pancreatic ductal adenocarcinoma

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