Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Dec. 6, 2021

Abstract Despite unprecedented responses of some cancers to immune checkpoint blockade (ICB) therapies, the application inhibitors in pancreatic cancer has been unsuccessful. Glucocorticoids and glucocorticoid receptor (GR) signaling are long thought suppress immunity by acting on cells. Here we demonstrate a previously undescribed tumor cell-intrinsic role for GR activating PD-L1 expression repressing major histocompatibility complex class I (MHC-I) ductal adenocarcinoma (PDAC) cells through transcriptional regulation. In mouse models PDAC, either cell-specific depletion or pharmacologic inhibition leads downregulation MHC-I upregulation cells, which turn promotes infiltration activity cytotoxic T enhances anti-tumor immunity, overcomes resistance ICB therapy. patients with correlates high expression, low poor survival. Our results reveal as tumor-intrinsic mechanism immunosuppression suggest that therapeutic targeting is promising way sensitize immunotherapy.

Language: Английский

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The induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Feb. 9, 2022

Despite the remarkable success of immunotherapy in many types cancer, pancreatic ductal adenocarcinoma has yet to benefit. Innate immune cells are critical anti-tumor immunosurveillance and recent studies have revealed that these populations possess a form memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, metabolic reprograming. Here we demonstrate yeast-derived particulate β-glucan, an inducer traffics pancreas, causes CCR2-dependent influx monocytes/macrophages pancreas display features immunity. These can be activated upon exposure tumor tumor-derived factors, show enhanced cytotoxicity against cells. In orthotopic models adenocarcinoma, β-glucan treated mice significantly reduced burden prolonged survival, is further when combined with immunotherapy. findings characterize dynamic mechanisms localization peripheral immunity identify application cancer.

Language: Английский

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KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered?

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: Nov. 29, 2022

KRAS mutations are among the most commonly occurring in cancer. After being deemed undruggable for decades, G12C specific inhibitors showed that small molecule can be developed against this notorious target. At same time, there is still no agent could target G12D which common mutation and found majority of KRAS-mutated pancreatic tumors. Nevertheless, significant progress now made space with development several compounds bind to inhibit G12D, notably MRTX1133. Exciting advances field also include an immunotherapeutic approach uses adoptive T-cell transfer specifically In mini-review, we discuss recent targeting potential further clinical various approaches.

Language: Английский

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Immunosuppression, immune escape, and immunotherapy in pancreatic cancer: focused on the tumor microenvironment

Cellular Oncology, Journal Year: 2022, Volume and Issue: 46(1), P. 17 - 48

Published: Nov. 11, 2022

Language: Английский

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Follicular Helper T Cells Remodel the Immune Microenvironment of Pancreatic Cancer via Secreting CXCL13 and IL-21

Cancers, Journal Year: 2021, Volume and Issue: 13(15), P. 3678 - 3678

Published: July 22, 2021

Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play anti-tumor role in various malignant solid tumors and predict better patient prognosis. In present study, we aimed to determine immunosuppressive mechanism associated with Tfh explore a new strategy improve tumor microenvironment PDAC. Flow cytometry was used detect infiltration proportion tissues peripheral blood from patients The spatial correlations related immune were evaluated using immunofluorescence. function examined vitro vivo model systems. high predicted recruited CD8+ B by secreting C-X-C motif chemokine ligand 13 (CXCL13), promoted maturation into antibody-producing plasma interleukin 21 (IL-21), thereby promoting formation immunoactive microenvironment. inhibited programmed cell death 1 (PD-L1)/programmed (PD-1) signaling pathway PDAC, which could be reversed neoadjuvant chemotherapy. Treatment recombinant CXCL13, IL-21 alleviated growth enhanced cells, as well PDAC mouse model. Our results revealed mediating cellular immunity humoral via CXCL13 determined novel immunosuppression

Language: Английский

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The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges

Cancers, Journal Year: 2022, Volume and Issue: 14(4), P. 995 - 995

Published: Feb. 16, 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancer worldwide with an overall survival rate, all stages combined, still <10% at 5 years. The poor prognosis attributed to challenges in early detection, a low opportunity for radical resection, limited response chemotherapy, radiotherapy, resistance immune therapy. Moreover, pancreatic tumoral cells are surrounded by abundant desmoplastic stroma, which responsible creating mechanical barrier, preventing appropriate vascularization leading cell infiltration. Accumulated evidence suggests that PDAC impaired multiple "immune defects", including lack high-quality effector (CD4, CD8 T cells, dendritic cells), barriers infiltration due reaction, dominance such as regulatory myeloid-derived suppressor M2 macrophages, resulting immunosuppressive tumor microenvironment (TME). Although recent studies have brought new insights into TME, its understanding remains not fully elucidated. Further required better human might help develop potent therapeutic strategies correcting these defects hope unlock (immune) In this review, we describe main actors involved well their implications potential biomarkers targets.

Language: Английский

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Balance between immunoregulatory B cells and plasma cells drives pancreatic tumor immunity

Cell Reports Medicine, Journal Year: 2022, Volume and Issue: 3(9), P. 100744 - 100744

Published: Sept. 1, 2022

Plasma cell responses are associated with anti-tumor immunity and favorable response to immunotherapy. B cells can amplify immune through antibody production; yet in patients tumor-bearing mice often fail support this effector function. We identify dysregulated transcriptional program that disrupts differentiation of naive into plasma cells. The signaling network contributing dysfunction is driven by interleukin (IL) 35 stimulation a STAT3-PAX5 complex upregulates the regulator BCL6 Transient inhibition tumor-educated sufficient reverse differentiation, stimulating intra-tumoral accumulation T rendering pancreatic tumors sensitive anti-programmed death protein 1 (PD-1) blockade. Our findings argue cancer be due an active systemic suppression targeted synergize cell-directed

Language: Английский

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Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade

Cancer Immunology Research, Journal Year: 2023, Volume and Issue: 11(4), P. 435 - 449

Published: Jan. 23, 2023

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and much more detailed understanding of the tumor microenvironment is needed if this situation be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time flight (CyTOF) single-cell RNA sequencing. T cells were predominant cell subset observed within tumors. Over 30% CD4+ expressed CCR6+CD161+ Th17 phenotype 17% displayed an activated regulatory profile. Large CD8+ tissue-resident memory (TRM) also present high levels programmed death protein 1 (PD-1) TIGIT. A population putative tumor-reactive CD103+CD39+ was lymphocytes population. The expression PD-1 ligands limited largely hemopoietic whilst TIGIT widely microenvironment. Programmed death-ligand CD155 area ectopic lymphoid structures colocalized PD-1+TIGIT+ cells. Combinatorial anti–PD-1 enhanced IFNγ secretion proliferation presence ligands. As such, showed that substantial TRM exhausted where dual receptor represents promising avenue for future immunotherapy.

Language: Английский

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A T Cell‐Engaging Tumor Organoid Platform for Pancreatic Cancer Immunotherapy

Advanced Science, Journal Year: 2023, Volume and Issue: 10(23)

Published: June 4, 2023

Abstract Pancreatic ductal adenocarcinoma (PDA) is a clinically challenging disease with limited treatment options. Despite small percentage of cases defective mismatch DNA repair (dMMR), PDA included in the most immune‐resistant cancer types that are poorly responsive to immune checkpoint blockade (ICB) therapy. To facilitate drug discovery combating this immunosuppressive tumor type, high‐throughput screen platform established newly developed T cell‐incorporated pancreatic organoid model. Tumor‐specific cells organoids by two‐step cell packaging, fully recapitulating infiltration microenvironment (TME). The generated key components original tumor, including epithelial, vascular endothelial, fibroblast and macrophage cells, then packaged into their outside layer mimicking physical barrier enabling cytotoxicity studies. In organoid‐based screen, epigenetic inhibitors ITF2357 I‐BET151 identified, which combination anti‐PD‐1 based therapy show considerably greater anti‐tumor effect. combinatorial turns TME from immunoactive, up‐regulates MHC‐I antigen processing presentation, enhances effector activity. standardized model has shown great promise accelerate for cancer.

Language: Английский

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The Interaction between Intratumoral Microbiome and Immunity Is Related to the Prognosis of Ovarian Cancer

Microbiology Spectrum, Journal Year: 2023, Volume and Issue: 11(2)

Published: March 28, 2023

Microbiota can influence the occurrence, development, and therapeutic response of a wide variety cancer types by modulating immune responses to tumors. Recent studies have demonstrated existence intratumor bacteria inside ovarian (OV). However, whether microbes are associated with tumor microenvironment (TME) prognosis OV still remains unknown. The RNA-sequencing data clinical survival 373 patients in Cancer Genome Atlas (TCGA) were collected downloaded. According knowledge-based functional gene expression signatures (Fges), was classified into two subtypes, termed immune-enriched immune-deficient subtypes. subtype, which had higher infiltration enriched CD8+ T cells M1 type macrophages (M1) mutational burden, exhibited better prognosis. Based on Kraken2 pipeline, microbiome profiles explored found be significantly different between A prediction model consisting 32 microbial constructed using Cox proportional-hazard showed great prognostic value for patients. strongly hosts' factors. Especially, five species (Achromobacter deleyi Microcella alkaliphila, Devosia sp. strain LEGU1, Ancylobacter pratisalsi, Acinetobacter seifertii). Cell experiments that seifertii inhibit macrophage migration. Our study could subtypes intratumoral microbiota Furthermore, closely IMPORTANCE microorganisms. role development their interaction largely -deficient enrichment subtype Microbiome analysis an independent predictor interact expression. microbes, Together, findings our highlight important roles TME OV, paving way further investigation its underlying mechanisms.

Language: Английский

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