The reciprocal regulation between host tissue and immune cells in pancreatic ductal adenocarcinoma: new insights and therapeutic implications

AbstractPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and is one of the most difficult-to-treat cancers. Surgical resection and adjuvant therapy have limited effects on the overall survival of PDAC patients. PDAC exhibits an immunosuppressive microenvironment, the immune response predicts survival, and activation of immune system has the potential to produce an efficacious PDAC therapy. However, chimeric antigen receptor T (CAR-T) cell immunotherapy and immune checkpoint blockade (ICB), which have produced unprecedented clinical benefits in a variety of different cancers, produce promising results in only some highly selected patients with PDAC. This lack of efficacy may be because existing immunotherapies mainly target the interactions between cancer cells and immune cells. However, PDAC is characterized by an abundant tumor stroma that includes a heterogeneous mixture of immune cells, fibroblasts, endothelial cells, neurons and some molecular events. Immune cells engage in extensive and dynamic crosstalk with stromal components in the tumor tissue in addition to tumor cells, which subsequently impacts tumor suppression or promotion to a large extent. Therefore, exploration of the interactions between the stroma and immune cells may offer new therapeutic opportunities for PDAC. In this review, we discuss how infiltrating immune cells influence PDAC development and explore the contributions of complex components to the immune landscape of tumor tissue. The roles of stromal constituents in immune modulation are emphasized. We also predict potential therapeutic strategies to target signals in the immune network in the abundant stromal microenvironment of PDAC.

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The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.821232 ◽

2022 ◽

Vol 9 ◽

Author(s):

Xuefei Liu ◽

Ziwei Luo ◽

Xuechen Ren ◽

Zhihang Chen ◽

Xiaoqiong Bao ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Rna Sequencing ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Cell ◽

Immune Checkpoint Blockade ◽

Ductal Adenocarcinoma ◽

Malignant Cells ◽

Sequencing Data ◽

Immunosuppressive Microenvironment

Background: Pancreatic ductal adenocarcinoma (PDAC) is dominated by an immunosuppressive microenvironment, which makes immune checkpoint blockade (ICB) often non-responsive. Understanding the mechanisms by which PDAC forms an immunosuppressive microenvironment is important for the development of new effective immunotherapy strategies.Methods: This study comprehensively evaluated the cell-cell communications between malignant cells and immune cells by integrative analyses of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC. A Malignant-Immune cell crosstalk (MIT) score was constructed to predict survival and therapy response in PDAC patients. Immunological characteristics, enriched pathways, and mutations were evaluated in high- and low MIT groups.Results: We found that PDAC had high level of immune cell infiltrations, mainly were tumor-promoting immune cells. Frequent communication between malignant cells and tumor-promoting immune cells were observed. 15 ligand-receptor pairs between malignant cells and tumor-promoting immune cells were identified. We selected genes highly expressed on malignant cells to construct a Malignant-Immune Crosstalk (MIT) score. MIT score was positively correlated with tumor-promoting immune infiltrations. PDAC patients with high MIT score usually had a worse response to immune checkpoint blockade (ICB) immunotherapy.Conclusion: The ligand-receptor pairs identified in this study may provide potential targets for the development of new immunotherapy strategy. MIT score was established to measure tumor-promoting immunocyte infiltration. It can serve as a prognostic indicator for long-term survival of PDAC, and a predictor to ICB immunotherapy response.

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Breaking the Barrier—PEGylated Recombinant Human Hyaluronidase (PEGPH20)—A New Therapeutic Approach to the Treatment of Pancreatic Ductal Adenocarcinoma

Oncology & Hematology Review (US) ◽

10.17925/ohr.2017.13.02.107 ◽

2017 ◽

Vol 13 (02) ◽

pp. 107 ◽

Cited By ~ 1

Author(s):

Andrew Hendifar ◽

Andrea Bullock ◽

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Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Immune Cells ◽

Fluid Pressure ◽

Tumor Stroma ◽

Phase Iii ◽

Ductal Adenocarcinoma ◽

Double Blind ◽

Potential Biomarker ◽

Advanced Therapy ◽

Recombinant Human Hyaluronidase

New therapeutic approaches are urgently needed to improve survival for patients with metastatic pancreatic ductal adenocarcinoma (PDA). This carcinoma is characterized by a hyaluronan (HA)-rich desmoplastic stroma that raises tumor interstitial fluid pressure (IFP), which in turn compresses the vasculature and impedes access of anti-cancer therapies and immune cells to tumor sites. It is this biophysical barrier that is the target for PEGylated recombinant human hyaluronidase (PEGPH20; pegvorhyaluronidase alfa), which degrades HA polymers to tetra- and hexa-saccharides to remodel the tumor stroma. In preclinical models, PEGPH20 reduced IFP, and expanded tumor vasculature to improve perfusion, which increased access for innate immune cells, antibodies and therapeutic agents. The results of a phase Ib study have suggested benefits in overall survival and progression-free survival (PFS) for patients with tumors that accumulate HA (termed HA-High) treated with a combination of gemcitabine and PEGPH20. A phase II study (HALO 109-202) demonstrated that HA could be a potential biomarker for identifying patients who may be most suitable for PEGPH20 treatment. HALO 109-202 showed positive outcomes for PFS especially in HA-High patients treated with PEGPH20 plus nab-paclitaxel and gemcitabine. A randomized, double-blind, phase III study (HALO 109-301) exploring the benefits of PEGPH20 in HA-High patients with PDA is ongoing. Other PEGPH20-based combinations are being investigated in multiple stroma-rich cancers, including lung, gastric, and breast. PEGPH20 is the most advanced therapy targeting the tumor stroma and has the potential to form the therapeutic backbone for the treatment of stroma-rich tumors.

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Gamma-delta T cells stimulate IL-6 production by pancreatic stellate cells in pancreatic ductal adenocarcinoma

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-020-03367-8 ◽

2020 ◽

Vol 146 (12) ◽

pp. 3233-3240

Author(s):

Adrian M. Seifert ◽

Julian List ◽

Max Heiduk ◽

Rahel Decker ◽

Janusz von Renesse ◽

...

Keyword(s):

Extracellular Matrix ◽

T Cells ◽

Pancreatic Ductal Adenocarcinoma ◽

Pancreatic Tumor ◽

Tumor Tissue ◽

Stellate Cell ◽

Γδ T Cells ◽

Tumor Stroma ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma

Abstract Introduction The immunosuppressive tumor microenvironment promotes progression of pancreatic ductal adenocarcinoma (PDAC). γδ T cells infiltrate the pancreatic tumor stroma and support tumorigenesis through αβ T cell inhibition. Pancreatic stellate cell (PSC) activation contributes to pancreatic fibrosis in PDAC, limiting the delivery and efficacy of therapeutic agents. Whether γδ T cells have direct effects on PSC activation is unknown. Methods In this study, we analyzed tumor tissue from 68 patients with PDAC and determined the frequency and location of γδ T cells using immunohistochemistry and immunofluorescence. PDAC samples from the TCGA database with low and high TRGC2 expression were correlated with the expression of extracellular matrix genes. Further, PSCs were isolated from pancreatic tumor tissue and co-cultured with γδ T cells for 48 hours and cytokine production was measured using a cytometric bead array. Results γδ T cells infiltrated the pancreatic tumor stroma and were located in proximity to PSCs. A high infiltration of γδ T cells was associated with increased expression of several extracellular matrix genes in human PDAC. In vitro, γδ T cells stimulated IL-6 production by PDAC-derived PSCs. Conclusion γδ T cells activated PSCs and modulation of this interaction may enhance the efficacy of combinational therapies in human PDAC.

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Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress

Cancers ◽

10.3390/cancers13174434 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4434

Author(s):

Siddharth Mehra ◽

Nilesh Deshpande ◽

Nagaraj Nagathihalli

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Pi3k Pathway ◽

Tumor Burden ◽

Ductal Adenocarcinoma ◽

Cancer Type ◽

Therapeutic Implications ◽

Downstream Signaling ◽

Genetic Mouse Model ◽

Dismal Prognosis ◽

Effector Pathways

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest solid tumors that remain treatment-refractory and show a dismal prognosis. More than 90% of PDAC tumors harbor mutations in the K-Ras that exert a strong pro-tumorigenic effect by activating several downstream effector pathways, including phosphatidylinositol-3-kinase (PI3K)-Akt. The role of frequently activated PI3K/Akt pathway in promoting PDAC aggressiveness is well established. Therapeutic approaches targeting PI3K and downstream signaling components in different cellular compartments, including tumor, stromal and immune cells, have directly impacted the tumor burden in this cancer type. Our previous work has demonstrated that targeting the PI3K/Akt/mTOR pathway reduced tumor growth and improved survival in the genetic mouse model of PDAC. Here, we discuss the significance of targeting PI3K signaling and the biological impact of PI3K inhibition in modulating the tumor–stromal immune crosstalk within the microenvironment of pancreatic cancer. Furthermore, this review updates on the current challenges involving the therapeutic implications of targeting this pathway in PDAC.

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