Histamine targets myeloid-derived suppressor cells and improves the anti-tumor efficacy of PD-1/PD-L1 checkpoint blockade.
Ontology highlight
ABSTRACT:
SUBMITTER: Grauers Wiktorin H
PROVIDER: S-EPMC6394491 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
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Project description:Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.
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Project description:Receptor activator of NF-?B ligand (RANKL) and its receptor RANK, are members of the tumor necrosis factor and receptor superfamilies, respectively. Antibodies targeting RANKL have recently been evaluated in combination with anti-CTLA4 in case reports of human melanoma and mouse models of cancer. However, the efficacy of anti-RANKL in combination with antibodies targeting other immune checkpoint receptors such as PD1 has not been reported. In this study, we demonstrated that blockade of RANKL improves anti-metastatic activity of antibodies targeting PD1/PD-L1 and improves subcutaneous growth suppression in mouse models of melanoma, prostate and colon cancer. Suppression of experimental lung metastasis following combination anti-RANKL with anti-PD1 requires NK cells and IFN-?, whereas subcutaneous tumor growth suppression with this combination therapy is attenuated in the absence of T cells and IFN-?. Furthermore, addition of anti-RANKL to anti-PD1 and anti-CTLA4 resulted in superior anti-tumor responses, irrespective of the ability of anti-CTLA4 isotype to engage activating FcR, and concurrent or delayed RANKL blockade was most effective. Early-during-treatment assessment reveals this triple combination therapy compared to dual anti-PD1 and anti-CTLA4 combination therapy further increased the proportion of tumor-infiltrating CD4+ and CD8+ T cells that can produce both IFN-? and TNF. Finally, RANKL expression appears to identify tumor-specific CD8+ T cells expressing higher levels of PD1 which can be modulated by anti-PD1. These data set the scene for clinical evaluation of denosumab use in patients receiving contemporary immune checkpoint blockade.
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Project description:BackgroundDysregulated expression and activation of receptor tyrosine kinases (RTKs) are associated with a range of human cancers. However, current RTK-targeting strategies exert little effect on pancreatic cancer, a highly malignant tumor with complex immune microenvironment. Given that immunotherapy for pancreatic cancer still remains challenging, this study aimed to elucidate the prognostic role of RTKs in pancreatic tumors with different immunological backgrounds and investigate their targeting potential in pancreatic cancer immunotherapy.MethodsKaplan-Meier plotter was used to analyze the prognostic significance of each of the all-known RTKs to date in immune "hot" and "cold" pancreatic cancers. Gene Expression Profiling Interactive Analysis-2 was applied to assess the differential expression of RTKs between pancreatic tumors and normal pancreatic tissues, as well as its correlation with immune checkpoints (ICPs). One hundred and fifty in-house clinical tissue specimens of pancreatic cancer were collected for expression and correlation validation via immunohistochemical analysis. Two pancreatic cancer cell lines were used to demonstrate the regulatory effects of RTKs on ICPs by biochemistry and flow cytometry. Two in vivo models bearing pancreatic tumors were jointly applied to investigate the combinational regimen of RTK inhibition and immune checkpoint blockade for pancreatic cancer immunotherapy.ResultsMET was identified as a pancreatic cancer-specific RTK, which is significantly associated with prognosis in both immune "hot" and "cold" pancreatic cancers. MET was observed to be highly upregulated in pancreatic cancer tissues, and positively correlated with PD-L1 levels. Elevated MET and PD-L1 expressions were closely associated with lymph node metastasis, tumor TNM stage, and overall survival in pancreatic cancer. Mechanistically, MET could interact with PD-L1, and maintain its expression level in multiple ways. MET deficiency was found to facilitate lymphocyte infiltration into pancreatic tumors. Finally, significant benefits of combining MET inhibition with PD-1/PD-L1 blockage were verified in both orthotopic and subcutaneous mouse models of pancreatic cancer.ConclusionsThis study systematically investigated the potential effectiveness of a novel pancreatic cancer immunotherapy targeting RTKs, and revealed the function of MET in PD-L1 regulation as well as the combined therapeutic efficacy of MET and PD-L1 in pancreatic cancer.
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Project description:Background & aimsImmune checkpoint blockade (ICB) has been approved for treatment of hepatocellular carcinoma (HCC). However, many patients with advanced HCC are non-responders to ICB monotherapy. Cytotoxic chemotherapy has been proposed to modulate the tumor microenvironment (TME) and sensitize tumors to ICB. Thus, we aimed to study the combination of cytotoxic chemotherapy and ICB in an orthotopic HCC model.MethodsPreclinical orthotopic HCC mouse models were used to elucidate the efficacy of 5-fluorouracil (5-FU) and ICB. The mice were intrahepatically injected with RIL-175 or Hepa1-6 cells, followed by treatment with 5-FU and anti-programmed cell death ligand 1 (PD-L1) antibody. Myeloid-derived suppressor cells (MDSCs) were depleted to validate their role in attenuating sensitivity to immunotherapy. Flow cytometry-based immune profiling and immunofluorescence staining were performed in mice and patient samples, respectively.Results5-FU could induce intratumoral MDSC accumulation to counteract the infiltration of T lymphocytes and natural killer cells, thus abrogating the anti-tumor efficacy of PD-L1 blockade. In clinical samples, MDSCs accumulated and CD8+ T cell numbers decreased following transarterial chemoembolization.Conclusion5-FU can trigger the accumulation of immunosuppressive MDSCs, impairing the response to PD-L1 blockade in HCC. Our data suggest that the combination of specific chemotherapy and ICB may impair anti-tumor immune responses, warranting further study in preclinical models and consideration in clinical settings.Lay summaryOur findings suggest that some chemotherapies may impair the anti-tumor efficacy of immunotherapy. Further studies are required to uncover the specific effects of different chemotherapies on the immunological profile of tumors. This data will be critical for the rational design of combination immunotherapy strategies for patients with hepatocellular carcinoma.
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Project description:Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. SIGNIFICANCE: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states.
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Project description:Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma.PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management.This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.
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Project description:Immune checkpoint inhibition represents a major recent breakthrough in the treatment of malignant diseases including breast cancer. Blocking the programmed death receptor-1 (PD-1) and its ligand, PD-L1, has shown impressive antitumor activity and may lead to durable long-term disease control, especially in the triple-negative subtypes of breast cancer (TNBC). Although immune checkpoint blockade is generally well tolerated, specific immune-related adverse events (irAEs) may occur. This review summarizes the clinical efficacy, perspectives, and future challenges of using PD-1/PD-L1-directed antibodies in the treatment of breast cancer.
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Project description:Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone. However, there remains little consensus on the mechanism(s) of response with this combination. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.
2024-03-04 | GSE260816 | GEO
Project description:BackgroundImmune checkpoint inhibitors that target programmed cell death protein 1 (PD-1) have obtained encouraging results, but a fraction of tumor patients failed to respond to anti-PD-1 treatment due to the existence of multiple immune suppressive elements such as myeloid-derived suppressor cells (MDSCs). Traditional Chinese medicine or natural products from medicinal plants could enhance immunity and may be helpful for cancer immunotherapy. As a digestive metabolite from cruciferous plants, 3,3'-diindolylmethane (DIM) has been widely used in chemotherapy, but its influence on cancer immunotherapy remains unclear. Here we investigate the function of DIM on MDSCs and examine the therapeutic effects of DIM in conjunction with PD-1 antibody against mouse tumors.MethodsFlow cytometry analysis, Western blot analysis and qRT-PCR assay were used to examine the inhibitory effects and mechanisms of DIM on MDSCs in vitro and in vivo. The therapeutic effects of DIM on cancer immunotherapy by PD-1 antibody were evaluated in mouse models of breast cancer and melanoma tumor.ResultsDIM exerted the inhibitory effect on MDSCs via downregulating miR-21 level and subsequently activating PTEN/PIAS3-STAT3 pathways. Adoptive transfer of MDSCs impaired the therapeutic effects of DIM, indicating that the antitumor activity of DIM might be due to the suppression of MDSCs. Furthermore, in mouse models of breast cancer and melanoma tumor, the addition of DIM can enhance the therapeutic effect of PD-1 antibody through promoting T cells responses, and thereby inhibiting tumor growth.ConclusionsOverall, the strategy based on the combination treatment of anti-PD-1 antibody and DIM may provide a new approach for cancer immunotherapy. Cruciferae plants-rich diet which contains high amount of DIM precursor may be beneficial for cancer patients that undergo the anti-PD-1 treatment.
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Project description:PD-1/PD-L1 checkpoint blockades have achieved significant progress in several kinds of tumours. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with positive PD-L1 expression. However, PD-1/PD-L1 checkpoint blockades have not achieved breakthroughs in treating glioblastoma because glioblastoma has a low immunogenic response and an immunosuppressive microenvironment caused by the precise crosstalk between cytokines and immune cells. A phase III clinical trial, Checkmate 143, reported that nivolumab, which targets PD-1, did not demonstrate survival benefits compared with bavacizumab in recurrent glioblastoma patients. Thus, the combination of a PD-1/PD-L1 checkpoint blockade with RT, TMZ, antibodies targeting other inhibitory or stimulatory molecules, targeted therapy, and vaccines may be an appealing solution aimed at achieving optimal clinical benefit. There are many ongoing clinical trials exploring the efficacy of various approaches based on PD-1/PD-L1 checkpoint blockades in primary or recurrent glioblastoma patients. Many challenges need to be overcome, including the identification of discrepancies between different genomic subtypes in their response to PD-1/PD-L1 checkpoint blockades, the selection of PD-1/PD-L1 checkpoint blockades for primary versus recurrent glioblastoma, and the identification of the optimal combination and sequence of combination therapy. In this review, we describe the immunosuppressive molecular characteristics of the tumour microenvironment (TME), candidate biomarkers of PD-1/PD-L1 checkpoint blockades, ongoing clinical trials and challenges of PD-1/PD-L1 checkpoint blockades in glioblastoma.
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