scholarly journals Immune Selection Pressure Contributes to Pancreatic Cancer Immune Evasion

2020 ◽  
Author(s):  
Reham Ajina ◽  
Annie Zuo ◽  
Shangzi Wang ◽  
Maha Moussa ◽  
Connor J. Cooper ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell ◽  
Immune Evasion ◽  
Selection Pressure ◽  
The United States ◽  
Janus Kinase ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Immune Selection ◽  
Cell Immunity

AbstractPancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune evasion in pancreatic cancer is induced in response to T cell-based immune selection pressure, and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide the first evidence that T cell-dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune evasion. mT3-2D cells derived from a Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre (KPC) mouse model of pancreatic cancer were grown in immunocompetent and immunodeficient C57BL/6 mice, and analyzed to determine the impacts of adaptive immunity specifically on malignant epithelial cells as well as on whole tumors. We found that immune selection pressure, via signal transducer and activator of transcription 1 (STAT1), stimulates malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and alters intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA approved drug, ruxolitinib, overcomes these tumor-protective responses and improves anti-PD1 antibody therapeutic efficacy. These findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.

scholarly journals Interactions between Cancer-Associated Fibroblasts and T Cells in the Pancreatic Tumor Microenvironment and the Role of Chemokines

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2995
Author(s):  
Laia Gorchs ◽  
Helen Kaipe
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Cell Trafficking ◽  
Cancer Associated Fibroblasts ◽  
Cell Axis ◽  
Combinational Treatment

Less than 10% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive 5 years or more, making it one of the most fatal cancers. Accumulation of T cells in pancreatic tumors is associated with better prognosis, but immunotherapies to enhance the anti-tumor activity of infiltrating T cells are failing in this devastating disease. Pancreatic tumors are characterized by a desmoplastic stroma, which mainly consists of activated cancer-associated fibroblasts (CAFs). Pancreatic CAFs have emerged as important regulators of the tumor microenvironment by contributing to immune evasion through the release of chemokines, cytokines, and growth factors, which alters T-cell migration, differentiation and cytotoxic activity. However, recent discoveries have also revealed that subsets of CAFs with diverse functions can either restrain or promote tumor progression. Here, we discuss our current knowledge about the interactions between CAFs and T cells in PDAC and summarize different therapy strategies targeting the CAF–T cell axis with focus on CAF-derived soluble immunosuppressive factors and chemokines. Identifying the functions of different CAF subsets and understanding their roles in T-cell trafficking within the tumor may be fundamental for the development of an effective combinational treatment for PDAC.

scholarly journals Mutational escape from CD8+ T cell immunity

2005 ◽  
Vol 201 (11) ◽  
pp. 1709-1714 ◽  
Author(s):  
David G. Bowen ◽  
Christopher M. Walker
Keyword(s):  
Mhc Class I ◽  
T Lymphocyte ◽  
Selection Pressure ◽  
Cytotoxic T Lymphocyte ◽  
Viral Persistence ◽  
Cd8 T Cell ◽  
Viral Escape ◽  
Immune Selection ◽  
Cell Immunity

The mechanisms by which the hepatitis C virus (HCV) establishes persistence are not yet fully understood. Previous chimpanzee and now human studies suggest that mutations within MHC class I–restricted HCV epitopes might contribute to viral escape from cytotoxic T lymphocyte (CTL) responses. However, there are several outstanding questions regarding the role of escape mutations in viral persistence and their fate in the absence of immune selection pressure.

scholarly journals Collagen Organization Does Not Influence T-Cell Distribution in Stroma of Human Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3648
Author(s):  
Eva-Maria Kamionka ◽  
Baifeng Qian ◽  
Wolfgang Gross ◽  
Frank Bergmann ◽  
Thilo Hackert ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Cell Distribution ◽  
Collagen Organization ◽  
T Cell Migration ◽  
Collagen Alignment

The dominant intrastromal T-cell infiltration in pancreatic cancer is mainly caused by the contact guidance through the excessive desmoplastic reaction and could represent one of the obstacles to an effective immune response in this tumor type. This study analyzed the collagen organization in normal and malignant pancreatic tissues as well as its influence on T-cell distribution in pancreatic cancer. Human pancreatic tissue was analyzed using immunofluorescence staining and multiphoton and SHG microscopy supported by multistep image processing. The influence of collagen alignment on activated T-cells was studied using 3D matrices and time-lapse microscopy. It was found that the stroma of malignant and normal pancreatic tissues was characterized by complex individual organization. T-cells were heterogeneously distributed in pancreatic cancer and there was no relationship between T-cell distribution and collagen organization. There was a difference in the angular orientation of collagen alignment in the peritumoral and tumor-cell-distant stroma regions in the pancreatic ductal adenocarcinoma tissue, but there was no correlation in the T-cell densities between these regions. The grade of collagen alignment did not influence the directionality of T-cell migration in the 3D collagen matrix. It can be concluded that differences in collagen organization do not change the spatial orientation of T-cell migration or influence stromal T-cell distribution in human pancreatic cancer. The results of the present study do not support the rationale of remodeling of stroma collagen organization for improvement of T-cell–tumor cell contact in pancreatic ductal adenocarcinoma.

scholarly journals The Present Status of Immuno-Oncolytic Viruses in the Treatment of Pancreatic Cancer

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1318
Author(s):  
Scott D. Haller ◽  
Michael L. Monaco ◽  
Karim Essani
Keyword(s):  
United States ◽  
Pancreatic Cancer ◽  
Surgical Resection ◽  
Clinical Investigation ◽  
Treatment Options ◽  
Late Phase ◽  
The United States ◽  
Oncolytic Viruses ◽  
Ductal Adenocarcinoma ◽  
Treatment Regimens

Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries. The incidence of PDAC has increased over the last 40 years and is projected to be the second leading cause of cancer death by 2030. Despite aggressive treatment regimens, prognosis for patients diagnosed with PDAC is very poor; PDAC has the lowest 5-year survival rate for any form of cancer in the United States (US). PDAC is very rarely detected in early stages when surgical resection can be performed. Only 20% of cases are suitable for surgical resection; this remains the only curative treatment when combined with adjuvant chemotherapy. Treatment regimens excluding surgical intervention such as chemotherapeutic treatments are associated with adverse effects and genetherapy strategies also struggle with lack of specificity and/or efficacy. The lack of effective treatments for this disease highlights the necessity for innovation in treatment options for patients diagnosed with early- to late-phase PDAC and immuno-oncolytic viruses (OVs) have been of particular interest since 2006 when the first oncolytic virus was approved as a therapy for nasopharyngeal cancers in China. Interest resurged in 2015 when T-Vec, an oncolytic herpes simplex virus, was approved in the United States for treatment of advanced melanoma. While many vectors have been explored, few show promise as treatment for pancreatic cancer, and fewer still have progressed to clinical trial evaluation. This review outlines recent strategies in the development of OVs targeting treatment of PDAC, current state of preclinical and clinical investigation and application.

scholarly journals CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response

2020 ◽  
Vol 117 (46) ◽  
pp. 28960-28970 ◽  
Author(s):  
Daniele Biasci ◽  
Martin Smoragiewicz ◽  
Claire M. Connell ◽  
Zhikai Wang ◽  
Ya Gao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Response ◽  
T Cell ◽  
Chemokine Receptors ◽  
Immune Cell ◽  
Antibody Therapy ◽  
Transcriptional Analysis ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Colorectal Cancers

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.

Phase I trial of gene-mediated cytotoxic immunotherapy in combination with chemoradiation for locally advanced pancreatic cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 195-195 ◽  
Author(s):  
M. Bloomston ◽  
C. Marsh ◽  
J. Walker ◽  
W. Coyle ◽  
H. Marx ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Median Survival ◽  
Tumor Vaccine ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Kinase Gene ◽  
Early Results ◽  
Cell Immunity ◽  
Dose Levels

195 Background: More than 80% of patients with pancreatic cancer present with locally advanced or metastatic disease and have a median survival of only 6 months. Immunotherapy approaches may improve outcomes. Gene Mediated Cytotoxic Immunotherapy (GMCI) is an approach that generates a systemic anti-tumor vaccine effect through intra-tumoral delivery of an adenoviral vector expressing the HSV-thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug and synergy with chemoradiation. The mechanisms of action involve tumor cytotoxicity, activation of antigen presenting cells and stimulation of systemic anti-tumor T-cell immunity. Safety with potential efficacy has been demonstrated in multiple clinical studies. This is the first application of GMCI in pancreatic cancer. Methods: This study evaluated 4 dose levels of AdV-tk (3x1010 to 1x1012 vector particles) injected into locally advanced tumors via EUS or CT-guidance before and during week 3 of standard 5-FU-chemoradiation. Valacyclovir (Valtrex, GSK) prodrug was given for 14 days after each of 2 AdV-tk injections. Results: The study completed accrual with 13 patients enrolled and 12 completing therapy with 3 at each of the 4 dose levels. One patient refused further participation during course 1 after recovering from azotemia. Median age was 64 years (range 55-81) and median baseline CA19-9 was 1634 U/ml. No dose limiting toxicities and no injection related complications occurred. Possibly related grade 3-4 toxicities, all of which were transient, included dehydration, azotemia and worsening elevation of bilirubin and AST. Kaplan-Meier estimated median survival is 12.2 months with 6 patients still alive at 8-20 months. Two patients achieved a partial response by RECIST criteria. One occurred in week 6 despite discontinuing 5-FU/radiation during week 1. The other had gradual decrease of a 7 cm tumor over 11 months. Serum CA19-9 levels decreased in 8/8 evaluable patients by 32-91% at 3 months after treatment initiation. Conclusions: AdV-tk can be safely injected into pancreatic tumors and combined with standard chemoradiation. Early results are highly encouraging and justify further evaluation in a phase II study. [Table: see text]

Tumor infiltration and cytokine biomarkers of prostate stem cell antigen (PSCA)-directed GOCAR-T cells in patients with advanced pancreatic tumors.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 734-734
Author(s):  
Joanne Shaw ◽  
Brandon Ballard ◽  
Xiaohui Yi ◽  
Aditya Malankar ◽  
Matthew R. Collinson-Pautz ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Phase 1 ◽  
Metastatic Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Fixed Dose ◽  
Serum Cytokines

734 Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic cancers. BPX-601 is an autologous GOCAR-T cell therapy engineered to express a PSCA-CD3ζ CAR and the MyD88/CD40 (iMC) costimulatory domain activated by rimiducid (Rim), designed to boost CAR-T performance in solid tumors. The safety and activity of BPX-601 activated with Rim in PSCA+ metastatic pancreatic cancer is being assessed in a Phase 1/2 clinical trial, BP-012 (NCT02744287). Methods: Phase 1 of BP-012 is a 3+3 dose escalation of BPX-601 (1.25-5 x106/kg) administered on Day 0 with a single, fixed-dose of Rim (0.4 mg/kg) on Day 7 in subjects with previously treated PSCA+ metastatic pancreatic cancer. All 5 subjects in cohort 5B received Flu/Cy lymphodepletion followed by BPX-601 (5 x106/kg) and Rim. BPX-601 kinetics, PBMC phenotype, and serum cytokines were assayed by qPCR, flow cytometry, and cytokine multiplex, respectively. Baseline and on-treatment biopsies were evaluated by RNAscope in situ hybridization. Results: BPX-601 cells expanded in all subjects and persisted up to 9 months (median 42 days). Transient reduction in BPX-601 vector copy number and total T cell count concurrent with Rim infusion, supports margination of activated BPX-601 cells. Increased serum cytokines, such as IFN-γ and GM-CSF, were observed following BPX-601 infusion with further elevation after Rim activation. All subjects with evaluable on-treatment biopsies had infiltration of BPX-601 cells (n = 3) proximal to tumor cells 7-15 days after Rim, but not in an end of treatment biopsy > 200 days after Rim (n = 1). Stratification by best response (RECIST 1.1) revealed stable disease in 3 subjects and progressive disease in 2 subjects was potentially associated with distinct cytokine signatures. Conclusions: BPX-601 GOCAR-T cells expand and persist in patients with PSCA+ metastatic pancreatic cancer and infiltrate metastatic lesions. A peripheral cytokine signature was observed following BPX-601 infusion. Select cytokines were enhanced after GOCAR-T cell activation and may correlate with clinical response. A cohort of subjects exploring serial administration of Rim is open for enrollment. Clinical trial information: NCT02744287.

scholarly journals Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer

Cancer Cell ◽  
2012 ◽  
Vol 21 (6) ◽  
pp. 822-835 ◽  
Author(s):  
Lauren J. Bayne ◽  
Gregory L. Beatty ◽  
Nirag Jhala ◽  
Carolyn E. Clark ◽  
Andrew D. Rhim ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell ◽  
T Cell Immunity ◽  
Colony Stimulating Factor ◽  
Cell Immunity ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes–Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer

2015 ◽  
Vol 33 (12) ◽  
pp. 1325-1333 ◽  
Author(s):  
Dung T. Le ◽  
Andrea Wang-Gillam ◽  
Vincent Picozzi ◽  
Tim F. Greten ◽  
Todd Crocenzi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Pancreatic Adenocarcinoma ◽  
Cell Immunity ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Elevated Liver Enzymes ◽  
Previously Treated Patients ◽  
Macrophage Colony ◽  
Grade 3

Purpose GVAX pancreas, granulocyte-macrophage colony-stimulating factor–secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes–expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. Patients and Methods Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response. Results A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. Conclusion Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.

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