scholarly journals Identification of a subset of immunosuppressive P2RX1-negative neutrophils in pancreatic cancer liver metastasis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xu Wang ◽  
Li-Peng Hu ◽  
Wei-Ting Qin ◽  
Qin Yang ◽  
De-Yu Chen ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Liver Metastases ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Neutralizing Antibody ◽  
Metastatic Tumor ◽  
Metabolic Reprogramming ◽  
Regulatory Mechanisms ◽  
Ductal Adenocarcinoma ◽  
Immunosuppressive Microenvironment

AbstractThe immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.

Relationship between liver metastases and PD-1 blockade in melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3072-3072 ◽  
Author(s):  
James Chi-Chiang Lee ◽  
Katy K. Tsai ◽  
Alain Patrick Algazi ◽  
Michael Rosenblum ◽  
Jeffrey Bluestone ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Liver Metastases ◽  
Stage Iv ◽  
Rejection Rate ◽  
Metastatic Tumor ◽  
Tumor Rejection ◽  
Cd8 Cells ◽  
The Mean ◽  
Organ Site ◽  
Response Site

3072 Background: WhilePD-1 blockade is effective in melanoma, durable responses remain elusive. We have previously reported that liver metastasis is associated with reduced response rates and that the fraction of CTLA4 hi/PD-1 hi CD8+ cells (“activated-exhausted” or T-ex cells) within the TIL is predictive of response to PD-1 blockade. Here, we explore the biology behind liver metastasis in human melanoma and in animal models. Methods: Patients with metastatic melanoma with or without liver metastasis were biopsied pre- PD-1 treatment and immune infiltrates were analyzed by FACS. The CD8 fraction was gated on CTLA4 and PD-1. C57BL/6 mice were implanted with a “primary” subcutaneous tumor and a “metastatic” tumor in the liver or the lungs (control), and given systemic PD-1 blockade therapy. Results: Patients with melanoma and liver metastasis (n = 25) had 15.2% T-ex cells while those without liver metastasis (n = 76) had 26.5 % T-ex cells, p = 0.0092. A T-ex fraction < 20% was significantly associated with lack of PD-1 response, p < 0.005. In C57BL/6 mice implanted with a B16 tumor (subQ & liver) treated with PD-1 antibody, 0/35 mice achieved subQ tumor rejection while in the SubQ only mice 9/30 mice (30%) rejected their tumors. The mean tumor size of mice with Sub Q+liver metastasis was 139.2 mm2 vs subQ only mice 23.4 mm2 at d 14, p = 0.002. Mice with liver metastasis showed a T-ex fraction 31.9% vs 67.3%without liver met, p = 0.0003. In contrast, in mice made lung metastatic, the subQ tumor rejection rate was 7/20 (35%), with T-ex infiltrate at 57.9%. The implantation of liver metastases from an unrelated MC38 tumor does not protect the subQ tumor from immune rejection. Conclusions: The presence of liver metastases is associated with reduced response to PD-1 blockade and reduced T-ex infiltrate in patients with stage IV melanoma. Mechanistic studies using a mouse model of syngeneic organ site specific metastasis confirms that the liver metastasis results in reduced antigen specific T cell at distant sites, resulting in reduced response. Site of metastasis may determine immune responsiveness in both mouse models and in humans with melanoma.

Targeting the IGF-axis potentiates immunotherapy for pancreatic ductal adenocarcinoma liver metastases by altering the immunosuppressive microenvironment.

2021 ◽  
pp. molcanther.MCT-20-0144-E.2020
Author(s):  
Masakazu Hashimoto ◽  
John David Konda ◽  
Stephanie Perrino ◽  
Maria Celia Fernandez ◽  
Andrew M Lowy ◽  
...  
Keyword(s):  
Liver Metastases ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Immunosuppressive Microenvironment

scholarly journals Co-evolution of tumor cells and hepatocytes fostered by SLIT2-ROBO1 axis facilitates liver metastasis of pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Qing Li ◽  
Xiao-Xin Zhang ◽  
Li-Peng Hu ◽  
Bo Ni ◽  
Xu Wang ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Mouse Models ◽  
Ex Vivo ◽  
Neutralizing Antibody ◽  
Transcriptional Analysis ◽  
Ductal Adenocarcinoma ◽  
Mechanism Study ◽  
Metastatic Niche

Abstract To explore the mechanism of co-evolution and potential driver of which in pancreatic ductal adenocarcinoma (PDAC) metastasis to liver, we studied key molecules involved in this progress and their translational values. Pre-metastatic niche (PMN) and macro metastatic niche (MMN) formation in mouse model were recognized via CT combined 3D organ reconstruction bioluminescence imaging. We next confirmed the expressions and distributions of SLIT2 and ROBO1 in 35 cases of human matched liver metastasis and primary PDAC samples, 14 case human PDAC liver metastasis transcriptional analysis, intrasplenic mouse models and KrasG12D/Trp53R172H/Pdx1-Cre (KPC) mouse models. Translational value was assessed on Slit2fl/fl/Alb1-Cre (Slit2 CKO) mice, KPC mouse model and Ex vivo tests via administration of neutralizing antibody targeting ROBO1. We also analyzed prognosis of 266 cases human PDAC tissue with or without SLIT2-ROBO1 fostered co-evolution and demonstrated the dependence receptor (DR) characteristics of ROBO1 in the following-up mechanism study. Experiments on Slit2 CKO, Slit2 CKO-RE and KPC mouse models demonstrated that disturbing SLIT2-ROBO1 mediated co-evolution in liver microenvironment via preventing their interaction could significantly attenuate liver metastasis of PDAC. We have demonstrated that co-evolution took advantage of DR characteristics in PMN and MMN. Targeting SLIT2-ROBO1 axis could be a therapeutic strategy towards metastatic PDAC.

scholarly journals Hsp70 Interacts with the TREM-1 Receptor Expressed on Monocytes and Thereby Stimulates Generation of Cytotoxic Lymphocytes Active against MHC-Negative Tumor Cells

2021 ◽  
Vol 22 (13) ◽  
pp. 6889
Author(s):  
Tatiana N. Sharapova ◽  
Elena A. Romanova ◽  
Olga K. Ivanova ◽  
Denis V. Yashin ◽  
Lidia P. Sashchenko
Keyword(s):  
Innate Immunity ◽  
Tumor Cells ◽  
Heat Shock Protein 70 ◽  
Antitumor Immunity ◽  
Lymphocyte Subpopulations ◽  
Regulatory Mechanisms ◽  
Cytotoxic Lymphocytes ◽  
Special Significance ◽  
Cytotoxic Lymphocyte ◽  
Negative Tumor

The search for and analysis of new ligands for innate immunity receptors are of special significance for understanding the regulatory mechanisms of immune response. Here we show that the major heat shock protein 70 (Hsp70) can bind to and activate TREM-1, the innate immunity receptor expressed on monocytes. The Hsp70–TREM-1 interaction activates expression of TNFα and IFNγ mRNAs in monocytes and stimulates IL-2 secretion by РВМСs. Moreover, incubation of РВМСs with Hsp70 leads to an appearance of cytotoxic lymphocyte subpopulations active against the MHC-negative tumor cells. In addition, both the CD4+ Т-lymphocytes and CD14+ monocytes are necessary for the Hsp70 signal transduction and a consequent activation of the cytotoxic lymphocytes. We believe that data presented in this study will broaden the views on the involvement of Hsp70 in the antitumor immunity.

scholarly journals LncRNA MIR17HG promotes colorectal cancer liver metastasis by mediating a glycolysis-associated positive feedback circuit

Oncogene ◽  
2021 ◽  
Author(s):  
Senlin Zhao ◽  
Bingjie Guan ◽  
Yushuai Mi ◽  
Debing Shi ◽  
Ping Wei ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Metastatic Tumor ◽  
Feedback Circuit ◽  
Colorectal Cancer Liver Metastasis ◽  
Positive Feedback Circuit

AbstractGlycolysis plays a crucial role in reprogramming the metastatic tumor microenvironment. A series of lncRNAs have been identified to function as oncogenic molecules by regulating glycolysis. However, the roles of glycolysis-related lncRNAs in regulating colorectal cancer liver metastasis (CRLM) remain poorly understood. In the present study, the expression of the glycolysis-related lncRNA MIR17HG gradually increased from adjacent normal to CRC to the paired liver metastatic tissues, and high MIR17HG expression predicted poor survival, especially in patients with liver metastasis. Functionally, MIR17HG promoted glycolysis in CRC cells and enhanced their invasion and liver metastasis in vitro and in vivo. Mechanistically, MIR17HG functioned as a ceRNA to regulate HK1 expression by sponging miR-138-5p, resulting in glycolysis in CRC cells and leading to their invasion and liver metastasis. More interestingly, lactate accumulated via glycolysis activated the p38/Elk-1 signaling pathway to promote the transcriptional expression of MIR17HG in CRC cells, forming a positive feedback loop, which eventually resulted in persistent glycolysis and the invasion and liver metastasis of CRC cells. In conclusion, the present study indicates that the lactate-responsive lncRNA MIR17HG, acting as a ceRNA, promotes CRLM through a glycolysis-mediated positive feedback circuit and might be a novel biomarker and therapeutic target for CRLM.

scholarly journals Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel

2021 ◽  
Author(s):  
L. Sams ◽  
S. Kruger ◽  
V. Heinemann ◽  
D. Bararia ◽  
S. Haebe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Progression Free Survival ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Prognostic Information ◽  
Peripheral Blood Mononuclear

Abstract Purpose This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). Patients and methods Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. Results Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. Conclusions Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.

scholarly journals Mutant KRAS drives metabolic reprogramming and autophagic flux in premalignant pancreatic cells

2021 ◽  
Author(s):  
Tatsunori Suzuki ◽  
Takahiro Kishikawa ◽  
Tatsuyuki Sato ◽  
Norihiko Takeda ◽  
Yuki Sugiura ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Biological Effects ◽  
Redox Balance ◽  
Metabolic Reprogramming ◽  
Ductal Adenocarcinoma ◽  
Early Event ◽  
Autophagic Flux ◽  
Nutritional Interventions ◽  
Mutational Activation ◽  
Almost All

AbstractMutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC.

scholarly journals Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 14 (3) ◽  
pp. 280
Author(s):  
Rita Rebelo ◽  
Bárbara Polónia ◽  
Lúcio Lara Santos ◽  
M. Helena Vasconcelos ◽  
Cristina P. R. Xavier
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Pancreatic Ductal Adenocarcinoma ◽  
De Novo ◽  
Drug Repurposing ◽  
Metastatic Tumor ◽  
Therapeutic Options ◽  
Ductal Adenocarcinoma ◽  
Clinical Indication ◽  
Novel Treatments

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials.

scholarly journals Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. I. Alexander ◽  
D. B. Vendramini-Costa ◽  
R. Francescone ◽  
T. Luong ◽  
J. Franco-Barraza ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Ductal Adenocarcinoma ◽  
Transforming Growth Factor Beta1 ◽  
Cancer Associated Fibroblast ◽  
Specific Tumor ◽  
Immunosuppressive Microenvironment ◽  
Anti Tumor Activity ◽  
Immunosuppressive Cytokines

AbstractPancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFβ1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFβ1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFβ1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

scholarly journals The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1642
Author(s):  
Claudia Curcio ◽  
Silvia Brugiapaglia ◽  
Sara Bulfamante ◽  
Laura Follia ◽  
Paola Cappello ◽  
...  
Keyword(s):  
Antitumor Immunity ◽  
Human Cancer ◽  
Treatment Resistance ◽  
Glycolytic Enzymes ◽  
Ductal Adenocarcinoma ◽  
Cellular Immune Responses ◽  
Altered Glucose ◽  
Hypoxic Tumor ◽  
Cellular Immune ◽  
Glycolytic Rate

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism—resulting in its increased uptake—and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.

Sign in / Sign up

Export Citation Format

Share Document