Immunotherapy For Pancreatic Cancer Research Articles

Abstract 1426: Expansion of CD8+PD-1+ T cells restored TCR repertoire as a prognostic marker to adoptive T cell immunotherapy of advanced pancreatic cancer

Abstract Purpose: We have previously reported the clinical benefits of autologous adoptive T cell immunotherapy in advanced pancreatic cancer (APC). We therefore aimed to further identify the core functional population of CD8+ T cells which exerted on the aberrant TCR repertoire and subsequently contribute to favorable prognosis after adoptive T cell therapy(ACT). Experimental Design: PBMC from APC patients (n=25) treated on a protocol of S-1 plus adoptive T cell immunotherapy were expanded ex vivo with a cytokine cocktail. The different fractions of CD8+PD-1+, CD8+LAG-3+, CD8+TIM-3+ and CD8+4-1BB+ T cells from time dependent segment were quantitated and expression of co-inhibitory molecules and biological functions on tumor killing and comparative analysis TCR repertoire from each patient were measured. The multivariate Cox hazards regression analysis was performed to identify the key T cell subset that affected the TCR repertoire recovery and subsequently associated with clinical outcome. Results: The CD3+, CD3+CD4+, and CD3+CD8+ T cells within the expanded cell product reached peak levels by day 15. CD8+ T cells exhibited enhanced expression of PD-1, LAG-3, and TIM-3, but not 4-1BB, after ex vivo expansion. Survival analysis showed that patients with a ratio of post/pre CD8+PD-1+ T cells > 2 had significantly favorable progressive-free survival (PFS) (median PFS time 180 days vs 85 days, P=0.002) and overall survival (OS) (median OS time 238 days versus 142 days, P=0.024). The sorted CD8+PD-1+ T cells displayed enhanced anti-tumor activity, and increased IFN-γ secretion after co-culture with autologous tumor cell lines. TCR repertoire diversity simultaneously rose during the ex vivo expansion and was associated with an increase in CD8+ T cells and decline in CD8+/CD28- T cells. Moreover, an increased TCR diversity was associated with significantly favorable PFS (median PFS time 166 days vs 79 days, P=0.043) and OS (median OS time 216 days versus 112 days, P=0.031) and was associated with the extent of expansion of the CD8+PD-1+ T cells (r2=0.464, P=0.001). Cox proportional hazards analysis showed that post/pre CD8+PD-1+ T cells after expansion ex vivo was an independent prognostic marker associated with both OS(P=0.009) and PFS(P=0.012). Conclusion: CD8+PD-1+ T cells, after ex vivo expansion over 15 days, are tumor-reactive. The extent of CD8+PD-1+ T cell expansion could restore TCR repertoire and was an independent prognostic factor associated with clinical outcomes in APC patients treated with ACT. Citation Format: Guoliang Qiao. Expansion of CD8+PD-1+ T cells restored TCR repertoire as a prognostic marker to adoptive T cell immunotherapy of advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1426.

Abstract 3102A: Analysis of spatial relationships between infiltrating immune cells within the tumor microenvironment following combinatorial immunotherapy

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy, which is the third leading cause of cancer related deaths in the United Sates. As the number of new cases continues to rise, the current treatments of surgical resection, chemotherapy, and radiation have not drastically improved PDAC survival rates. PDAC is known to have a quiescent immune microenvironment, which is resistant to single-agent checkpoint inhibitors. We identified a combination approach using immune checkpoint inhibition and immune activing agonists to prime the tumor microenvironment (TME) to activate T-cells in order to overcome this “cold” environment. Here we investigate spatial relationships between CD8+, PD-1+ (programmed cell death protein), and PD-L1+ (programmed cell death ligand) cells in the TME following single agent and combinatorial immunotherapy protocols. Experimental Procedures: Our cohort includes 17 surgically resected patient tumor specimens from formalin-fixed paraffin-embedded tissue blocks. These patients either received GM-CSF vaccine (GVAX) with or without immune checkpoint inhibitor, anti-PD-1. Of the 11 patients analyzed, six received GAVX with anti-PD-1 while the others received GVAX alone. Automated immunohistochemical staining was performed for CD8, PD-1, and PD-L1. Analysis was performed using HALO image analysis software (Indica Labs) (HALO v2.0.1145.31). Proximal distance (Nearest Neighbor Analysis) of CD8+ to PD-1+ cells, CD8+ to PD-L1+ cells, PD-1+ to PD-L1+ cells within the tumor area was measured for each patient to generate average distance between cell types. Results: Of the 17 PDAC patients in our cohort, 11 patient specimens were analyzed. Nearest Neighbor Analysis between the two groups shows there is a trend of increased distance between CD8+ cells and PD-1+ cells and between CD8+ cells and PD-L1+ cells in patients receiving GVAX and anti-PD-1 compared to GVAX alone (p=0.032 and n.s., respectively). Proximal distance analysis of PD-1+ cells to PD-L1+ cells is ongoing. Conclusions: PDAC remains a considerable diagnostic and therapeutic challenge due to its poor survival outcomes. However, immunotherapy may provide an alternative strategy to improve survival for PDAC patients. Our results suggest that monotherapy with GVAX versus combination therapy with GVAX plus anti-PD-L1 leads to differences in the spatial relationship between CD8+ cells and PD-1+ and PD-L1+ cells, specifically, greater distance between CD8+ T cells and PD-L1+ and PD-1+ cells, suggesting the potential for greater functionality and less direct cell/cell suppression. More broadly, our results demonstrate the ability to detect differences in patient groups based on spatial analysis of distance between cell types, a technique that can be applied generally to the correlative analyses of immunotherapy protocols.. Further analysis of spatial relationships and immune cell infiltration in the TME following immunotherapy will help elucidate how these treatment protocols impact the architecture of the TME and will help guide therapeutic approaches to immunotherapy in pancreatic cancer. We demonstrate a technique of spatial analysis that will aid in dissecting these cellular relationships. Citation Format: Dwayne L. Thomas II, Adrian G. Murphy, Matthew J. Weiss, Jin He, Martin A. Makary, Richard A. Burkhart, Christopher L. Wolfgang, Elizabeth M. Jaffee, Lei Zheng, Elizabeth D. Thompson. Analysis of spatial relationships between infiltrating immune cells within the tumor microenvironment following combinatorial immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3102A.

Abstract 522: PI3K/Akt signaling in tumor cells promotes immune evasion by limiting infiltration, recognition and killing by T cells

Abstract The presence of tumor-infiltrating T cells is associated with favorable patient outcomes, yet most pancreatic cancers are immunologically silent and resistant to currently available immunotherapy. In this study, a syngeneic orthotopic implantation model of pancreatic cancer was used to show that PI3K/Akt signaling in tumor cells down-regulate immunogenicity to evade T cell surveillance. Genetic silencing of PI3K catalytic isoform Pik3ca in KrasG12D/Trp53R172H-driven pancreatic tumors leads to infiltration of T cells, complete tumor regression, and 100% survival of immunocompetent host mice. By contrast, Pik3ca-null tumors implanted in T cell-deficient mice progress and kill 100% of the animals. Adoptive transfer of tumor antigen-experienced T cells eliminates Pik3ca-null tumors in immunodeficient mice. Pik3ca silencing or inhibition of its effector, Akt, increases the expression of MHC Class I and CD80 on the surface of murine and human pancreatic cancer cells. Down-regulating MHC Class I and CD80 expression, or increasing Akt activity, in Pik3ca-null tumors increases their susceptibility to T cell-mediated regression in vivo. These results indicate that PI3K/Akt signaling in tumor cells limits T cell recognition and clearance of pancreatic cancer. Strategies that selectively target the PI3K/Akt signaling pathway in tumor cells may improve immunotherapy for pancreatic cancer. Citation Format: Nithya Sivaram, Patrick McLaughlin, Ya-Ping Jiang, Lisa Ballou, Kien Pham, Chen Liu, Adrianus van der Velden, Richard Lin. PI3K/Akt signaling in tumor cells promotes immune evasion by limiting infiltration, recognition and killing by T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 522.

Abstract 4584: Malignant pancreatic cancer cells respond to immune selection pressure to foster immunosuppression

Abstract Background: Host immunity is relevant to pancreatic cancer (PC). Pancreatic tumors are infiltrated with a high number of immune cells, and they play a potential important role in disease evolution. However, there is no FDA approved immunotherapy for PC yet, suggesting that a deeper understanding of immune-cancer interaction is needed. The aim of this study was to investigate the effects of immune selection pressure on malignant pancreatic epithelial cells and on subsequent cancer immune evasion mechanisms. Materials and Methods: 1 X105 mT3-2D murine pancreatic cancer cells (Kras+/G12D, p53+/-R172H (Boj et al. 2015)) were injected subcutaneously into syngeneic C57BL/6J (WT), B6.CB17-Prkdcscid/SzJ (SCID) and T cell-depleted WT mice (10 mice/group). Tumor growth was monitored over time. 1 cm3 tumors then were harvested, processed and studied. To consider the complex biology of pancreatic cancer immunology, we analyzed tumor specimens in their entirety by histopathological evaluation, multiple color flow cytometry, NanoString nCounter, and global proteomics profiling. Furthermore, to evaluate the influence of immune selection pressure on neoplastic cells, we selectively analyzed malignant epithelial cell gene expression in the cell line, and in cells isolated from tumors grown in WT and SCID mice, respectively, by RNAseq on mT3-2D-GFP+ fluorescence-activated cell sorter (FACS)-sorted cells. Also, whole exome sequencing was performed on WT tumors. Results Here we demonstrate that mT3-2D tumors engrafted in WT mice grow more slowly as compared with syngeneic SCID and T cell-depleted tumors, demonstrating that the reduced mT3-2D tumor growth rate in WT mice is T cell dependent. Putative cancer neoantigens were identified from whole exome sequences with pVACtools. Supporting evidence of tumor immunogenicity came from the observation that WT tumors are moderately infiltrated with T cells, by IHC and flow cytometry. Proteomics and NanoString nCounter analysis demonstrated the selective presence of myeloid suppressive cells in WT tumors, supporting their role in immune evasion. Notably, RNAseq showed selective upregulation of malignant epithelial cell-derived genes known to stimulate this immunosuppressive phenotype, including myeloid- and complement-related genes. Conclusion Despite the immunogenicity of the WT tumors and the infiltration of T cells in this PC model, T cell immunity incompletely controls tumor growth. Malignant epithelial cells mediate this cancer immunosuppressive phenotype in response to immune selection pressure, suggesting novel translational opportunities.

Effect of targeting CD40 for DC vaccination in pancreatic adenocarcinoma.

e15783 Background: Although immunotherapy yields striking results in various malignancies, results in pancreatic cancer have been disappointing. Both a highly immunosuppressive tumor microenvironment and a dense desmoplastic stroma have been found to prohibit proper T-cell infiltration in these tumors, thereby preventing immunotherapy efficacy. We hypothesize that a rational and translational multistep approach is needed to sensitize pancreatic cancer to immunotherapy. In an aggressive murine pancreatic ductal adenocarcinoma model, we assessed the effectiveness of dendritic cell (DC) vaccination in combination with αCD40 treatment, as these treatments are known to induce effector T cells and degrade stroma, respectively. Methods: Immune competent C57BL/6 mice were inoculated subcutaneously with pancreatic tumor cells (KPC3). Mice with established tumors were vaccinated with tumor-loaded monocyte derived DCs and consequently treated with αCD40 agonistic antibodies. Tumor sizes were monitored over time. Immune responses were determined by flow cytometry of cells in peripheral blood, spleen and tumor. NanoString Technologies were applied on tumor samples. Results: A significant delay in tumor growth was found in the combination therapy arm compared to untreated mice and mice treated with DCs or αCD40 alone. Monotherapy had no effect on tumor growth. Survival of mice treated with the combination therapy was also improved compared to untreated mice or mice treated with monotherapy (P < 0.001). Interim blood analysis showed significant increases in frequencies of activated and proliferating T cells in treated animals and those cells also displayed an effector memory phenotype. This was more pronounced for CD4 T cells in mice treated with DCs while αCD40 therapy induced a confined response in CD8 T cells. Increased frequencies of tumor infiltrating lymphocytes were found in all treated mice compared to untreated mice. mRNA expression analysis indicated less exhausted phenotype of intratumoral lymphoid cells in mice treated with DCs and αCD40 compared to monotherapy DCs or αCD40. Conclusions: These results demonstrate the potency of this novel form of combination immunotherapy and reveals a mechanistic insight into the requirements of effective immunotherapy in pancreatic cancer.

Inflammation, Biomarkers and Immuno-Oncology Pathways in Pancreatic Cancer.

It is estimated that pancreatic cancer will be the second leading cause of cancer-related deaths globally by 2030, highlighting the ongoing lack of effective treatment options for this devastating condition. There is a lack of reliable prognostic or predictive markers in pancreatic cancer to guide management decisions, whether for systemic chemotherapy, molecularly targeted therapies, or immunotherapies. To date, the results for targeted agents and immunotherapies in unselected populations of chemo-refractory pancreatic cancer have not met expectations. The reasons for this lack of efficacy of immunotherapy in pancreatic cancer are not completely understood. The challenges in pancreatic cancer include the physical barrier created by the dense desmoplastic stroma surrounding the tumor, chemokine-mediated exclusion of T cells, relatively poorer antigenicity compared to other solid tumors, paucity of infiltrating T cells within the tumor, ultimately leading to an immunosuppressive microenvironment. A better understanding of the role of inflammation in pancreatic cancer, its tumor microenvironment and individualized patient-related features, be they molecular, clinical or histopathological, would enable a more effective tailored approach to the management of pancreatic cancer. In this review, the role of inflammation, the immune tumor microenvironment and potential immune biomarkers in pancreatic cancer are explored.

RNAi-Mediated PD-L1 Inhibition for Pancreatic Cancer Immunotherapy

The recent past has seen impressive progress in the treatment of various malignancies using immunotherapy. One of the most promising approaches involves immune checkpoint inhibitors. However, the clinical results with these agents have demonstrated variability in the response. Pancreatic cancer, in particular, has proven resistant to initial immunotherapy approaches. Here, we describe an alternative strategy that relies on combining gemcitabine and a novel programmed death-ligand 1 (PD-L1) inhibitor, termed MN-siPDL1. MN-siPDL1 incorporates small interfering RNA against PD-L1 (siPDL1) conjugated to a magnetic nanocarrier (MN). We show that noninvasive magnetic resonance imaging (MRI) could be used to monitor therapeutic response. Combination therapy consisting of gemcitabine and MN-siPDL1 in a syngeneic murine pancreatic cancer model resulted in a significant reduction in tumor growth and an increase in survival. Following optimization, a 90% reduction in tumor volume was achieved 2 weeks after the beginning of treatment. Whereas 100% of the control animals had succumbed to their tumors by week 6 after the beginning of treatment, there was no mortality in the experimental group by week 5, and 67% of the experimental animals survived for 12 weeks. This method could provide therapeutic benefit against an intractable disease for which there are no effective treatments and which is characterized by a mere 1% 5-year survival.

Amphiphilic polyanhydride-based recombinant MUC4β-nanovaccine activates dendritic cells.

Mucin 4 (MUC4) is a high molecular weight glycoprotein that is differentially overexpressed in pancreatic cancer (PC), functionally contributes to disease progression, and correlates with poor survival. Further, due to its aberrant glycosylation and extensive splicing, MUC4 is a potential target for cancer immunotherapy. Our previous studies have demonstrated the utility of amphiphilic polyanhydride nanoparticles as a useful platform for the development of protein-based prophylactic and therapeutic vaccines. In the present study, we encapsulated purified recombinant human MUC4-beta (MUC4β) protein in polyanhydride (20:80 CPTEG:CPH) nanoparticles (MUC4β-nanovaccine) and evaluated its ability to activate dendritic cells and induce adaptive immunity. Immature dendritic cells when pulsed with MUC4β-nanovaccine exhibited significant increase in the surface expressions of MHC I and MHC II and costimulatory molecules (CD80 and CD86), as well as, secretion of pro-inflammatory cytokines (IFN-γ, IL-6, and IL-12) as compared to cells exposed to MUC4β alone or MUC4β mixed with blank nanoparticles (MUC4β+NP). Following immunization, as compared to the other formulations, MUC4β-nanovaccine elicited higher IgG2b to IgG1 ratio of anti-MUC4β-antibodies suggesting a predominantly Th1-like class switching. Thus, our findings demonstrate MUC4β-nanovaccine as a novel platform for PC immunotherapy.

PD-1 immunotherapy in pancreatic cancer: current status

Abstract Pancreatic ductal adenocarcinoma is the known kind of tumor biologically featured as high malignant degree, lack of effective methods for diagnosis and treatment, which reflects its unpleasant prognosis. Recently, with the breakthrough of burgeoning therapeutic methods, the flush of dawn for pancreatic cancer nearly arrives. Nowadays, besides surgery, neoadjuvant chemoradiotherapy, tumor vaccine therapy, and immunotherapy all show their active situation and obtain certain clinical efficacy, but that is still limited to pancreatic cancer. However, the appearance and development of programmed cell death-1 (PD-1) immune checkpoint inhibitor may final improve survival of pancreatic cancer. This article aims to deeply understand the value of PD-1 immune checkpoint inhibitor in pancreatic cancer and validly provide the evidence for treatment by means of performing a systematic review on the current status in the fields of the mechanism and application of anti-PD-1 in pancreatic cancer, associations with surgery, PD-1-related side effects and prospections.

The Role of the Microbiome in Immunologic Development and its Implication For Pancreatic Cancer Immunotherapy

Our understanding of the microbiome and its role in immunity, cancer initiation, and cancer progression has evolved significantly over the past century. The "germ theory of cancer" was first proposed in the early 20th century, and shortly thereafter the bacterium Helicobacter pylori, and later Fusobacterium nucleatum, were implicated in the development of gastric and colorectal cancers, respectively. However, with the development of reliable mouse models and affordable sequencing technologies, the most fascinating aspect of the microbiome-cancer relationship, where microbes undermine cancer immune surveillance and indirectly promote oncogenesis, has only recently been described. In this review, we highlight the essential role of the microbiome in immune system development and maturation. We review how microbe-induced immune activation promotes oncogenesis, focusing particularly on pancreatic carcinogenesis, and show that modulation of the microbiome augments the anti-cancer immune response and enables successful immunotherapy against pancreatic cancer.

VISTA Checkpoint Implicated in Pancreatic Cancer Immunotherapy Resistance

VISTA Checkpoint Implicated in Pancreatic Cancer Immunotherapy Resistance

Abstract A156: PDA tumor cell death as following combination anti-PD-1 blockade and CXCR4 blockade is a direct effect of CD8+ T-cells

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDA) is the fourth most common cause of cancer death in the United States. Despite the fact that the human PDA microenvironment contains a mixture of infiltrating immune cells, including activated effector CD8+ T-cells, attempts to apply immune checkpoint inhibitor therapy have not yet been successful in achieving a clinical response (1). Combining blockade of the immune checkpoint receptor PD-1 with blockade of the chemokine receptor CXCR4 in a mouse model of PDA produced T-cell-mediated tumor cell killing (2). We therefore hypothesized that, in a human PDA slice culture model system that maintains the intact tumor microenvironment (3), combination of CXCR4 blockade with PD-1 blockade would lead to anti-tumor T-cell activation. Methods: Cores (6 mm) were taken from freshly resected, sterile human PDA specimens and cut into 250 µm thick slices using a vibratome. The slices were treated with either IgG antibody isotype control, AMD3100 (a CXCR4 blocking small molecule drug) plus antibody isotype control, anti-PD-1 antibody, or a combination of anti-PD-1 antibody and AMD3100 for two days. The slices were then stained with fluorescently labelled antibodies for CD8 and EpCAM, as well as with SR-FLICA, a reagent that produces a fluorescent signal when bound to activated Caspase 3 and 7 enzymes. Live slices were maintained in a humidified, temperature-controlled CO2 chamber for time-lapse confocal imaging for 1 hour. Similarly, untreated slices were imaged for 90 minutes prior to and following combined anti-PD-1 and AMD3100 drug treatment. Each slice was imaged at 3 different positions to observe CD8+ T-cells, EpCAM+ tumor cells, and SR-FLICA+ apoptotic cells throughout the slice. Each cell type was counted at each position over the entire time course imaged. Results: Compared to antibody isotype control or monotherapy, slices treated with combined PD-1 and CXCR4 blockade contained a greater fraction of EpCAM+ tumor cells that were undergoing apoptosis, indicated by SR-FLICA positivity. This treatment also increased the proportion of EpCAM+ tumor cells with a CD8+ T-cell within 20 µm, and EpCAM+ cells had increased evidence of apoptosis when a CD8+ cell was nearby. When individual slices were imaged before and after combined PD-1 and CXCR4 blockade, a greater proportion of EpCAM+ cells were found to have a CD8+ cell nearby after treatment compared to before treatment, and the tumor cells with a CD8+ cell nearby were more like to be undergoing apoptosis compared to before treatment. Conclusion: Direct visualization of live pancreatic cancer slice cultures demonstrates that combined PD-1 and CXCR4 blockade enhances both the migration of CD8+ T-cells towards epithelial tumor cells and their anti-tumor cytotoxic activity.

Low P4HA2 and high PRTN3 expression predicts poor survival in patients with pancreatic cancer

Background: The tumor microenvironment in pancreatic cancer has a multifaceted role in disease development and progression. Prolyl 4-hydroxylase subunit alpha 2 (P4HA2) and proteinase 3 (PRTN3) are involved in the synthesis and degradation of collagen in the tumor microenvironment and have been identified as prognostic biomarker candidates for pancreatic cancer in our previous mass spectrometric study. This study aimed at validating prognostic performance of P4HA2 and PRTN3 in a larger cohort of patients.Methods: The expression of P4HA2 and PRTN3 was evaluated with tissue microarrays and immunohistochemistry in 140 patients with pancreatic cancer who underwent surgical resection. Kaplan–Meier and Cox proportional hazards regression modeling were used to explore the association of P4HA2 and PRTN3, either separately or combined, with clinicopathological factors and survival.Results: Most tumors were positive for P4HA2 (133/140, 95%), whereas 77 tumors (55%) were positive for PRTN3. Expression levels of P4HA2 and PRTN3 did not separately correlate with disease-free or overall survival, in either uni- or multivariable analysis. However, a low P4HA2 and high PRTN3 expression correlated with shorter disease-free survival (median 7.0 vs. 13.4 months, adjusted HR 3.24, 95% CI: 1.13–9.25, p = .028) and overall survival (median 8.5 vs. 25.8 months, adjusted HR 8.14, 95% CI: 3.41–19.44, p < .001).Conclusion: Our data show that a low P4HA2 and high PRTN3 expression correlates with poor survival in patients with pancreatic cancer, indicating the involvement of collagen deposition in the restraint of the tumor. The tumoral expression of PRTN3 reinforces the therapeutic potential of PR1-targeting immunotherapy in pancreatic cancer.

Exosomes and the Future of Immunotherapy in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, associated with a late diagnosis and a five-year survival rate of 8%. Currently available treatments fall short in improving the survival and quality of life of PDAC patients. The only possible curative option is still the surgical resection of the tumor. Exosomes are extracellular vesicles secreted by cells that transport proteins, lipids, and nucleic acids to other cells, triggering phenotypic changes in the recipient cells. Tumor cells often secrete increased amounts of exosomes. Tumor exosomes are now accepted as important players in the remodeling of PDAC tumor stroma, particularly in the establishment of an immunosuppressive microenvironment. This has sparked the interest in their usefulness as mediators of immunomodulatory effects for the treatment of PDAC. In fact, exosomes are now under study to understand their potential as nanocarriers to stimulate an immune response against cancer. This review highlights the latest findings regarding the function of exosomes in tumor-driven immunomodulation, and the challenges and advantages associated with the use of these vesicles to potentiate immunotherapy in PDAC.

B7-H3 is regulated by BRD4 and promotes TLR4 expression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies worldwide. PDAC is resistant to chemotherapy and radiotherapy which leads to the poor prognosis of PDAC patients and a 5-year survival rate of less than 5%. Exploring the mechanism of the pancreatic cancer tumorigenesis is the key to finding a novel therapeutic strategy for cancer treatment. B7-H3 belongs to the B7 family of immunoregulatory proteins, and the overexpression of B7-H3 is found in various types of cancer. The regulation of B7-H3 expression in pancreatic cancer is still unclear. Here, we showed that B7-H3 acted as a negative prognostic biomarker in PDAC and promoted cell proliferation, invasion and metastasis in pancreatic cancer. Next, we applied the drug screening method to identify bromodomain and extra-terminal motif (BET) inhibitors that decreased the protein and mRNA levels of B7-H3 in pancreatic cancer cells. Moreover, we verified that BRD4 was responsible for regulating the expression of B7-H3 at the transcriptional level. Finally, our data indicated that the BRD4/B7-H3 axis modulated the expression of TLR4 in pancreatic cancer cells. Taken together, our results elucidated the regulation of B7-H3 expression in pancreatic cancer and uncovered the importance of BRD4/B7-H3/TLR4 pathway. The targeting of B7-H3 by the BET inhibitors may be a novel therapeutic strategy to overcome the immunotherapy and chemotherapy resistance in pancreatic cancer.

HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the second leading cause of cancer-related deaths worldwide. Despite immune checkpoints based immunotherapy highlights a new therapeutic strategy and achieves a remarkable therapeutic effect in various types of malignant tumors. Pancreatic cancer is one of the non-immunogenic cancers and is resistant to immunotherapy. Programmed death ligand 1 (PD-L1) is expressed on the surface of tumor cells and its level is a key determinant of the checkpoint immunotherapy efficacy. Here, we reported that the specific inhibitor of histone deacetylase 3 (HDAC3) decreased the protein and mRNA level of PD-L1 in pancreatic cancer cells. Furthermore, we showed that HDAC3 was critical for PD-L1 regulation and positively correlated with PD-L1 in PDAC patient specimens. Finally, we demonstrated that HDAC3/signal transducer and activator of transcription 3 (STAT3) pathway transcriptionally regulated PD-L1 expression. Collectively, our data contributes to a better understanding of the function of HDAC3 in cancer immunity and the regulatory mechanism of PD-L1. More importantly, these data suggest that the HDAC3 inhibitors might be used to improve immunotherapy in pancreatic cancer.

Immunotherapy in pancreatic cancer: New hope or mission impossible?

Pancreatic cancer (PC), one of the most lethal diseases, remains a challenging problem. Novel cancer therapy targeting the immune system has been explored. Although immunotherapy has yielded a favorable response in pre-clinical models, no significant improvement has been confirmed in clinical trials for PC. This may be partly attributable to the unique immunosuppressive tumor microenvironment of PC. Studies focusing on combination therapy showed the ability to break the immunosuppressive tumor microenvironment and enhance the immune response, which can translate to clinical benefits. Moreover, the application of sequencing techniques and neo-antigen vaccines has achieved promising results in clinical trials, which promote the development of personalized immunotherapy. However, lack of effective biomarkers is another challenge for the realization of personalized immune medicine. Biomarkers are urgently needed to identify subgroup of patients who would benefit from immunotherapy. In this review, we discuss advances in immunotherapy for pancreatic cancer, as well as the challenges and prospects for personalized immune medicine.

Prospects and challenges of immunotherapy for pancreatic cancer

Prospects and challenges of immunotherapy for pancreatic cancer

Prognostic value of PD-L1 expression in patients with pancreatic cancer

Background:Programmed cell death ligand 1 (PD-L1) expression was reported to be associated with poor prognosis in various solid tumors. However, the prognosis value of PD-L1 in pancreatic cancer remained inconclusive. We performed a meta-analysis to assess the clinical value of PD-L1 as a novel prognostic biomarker of pancreatic cancer.Methods:PubMed, Embase, and Web of Science were searched up to October 2018. The HRs and 95% CIs for overall survival (OS) and cancer-specific survival (CSS) according to the expressional status of PD-L1 were pooled. The combined odd ratios (ORs) and 95% CIs were utilized to assess the association between PD-L1 and clinicopathological characteristics.Results:A total of 9 studies with 993 patients were included. Elevated PD-L1 expression was related with poor OS (HR = 1.63, 95% CI = 1.34–1.98, P < .001) and CSS (HR = 1.86, 95% CI = 1.34–2.57, P < .001). Furthermore, high PD-L1 expression was also demonstrated to be associated with positive N stage (OR = 1.81, 95% CI = 1.21–2.71, P = .004), advanced T stage (OR = 1.86, 95% CI = 1.08–3.19, P = .025), and low differentiation (OR = 2.24, 95% CI = 1.16–4.33, P = .017). However, PD-L1 has nonsignificant correlation with M stage, gender, or age.Conclusion:This study suggests that PD-L1 is a potential prognostic biomarker and may be helpful to clinicians aiming to select the appropriate immunotherapy for pancreatic cancer.

Immunotherapy of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second most common cause of cancer-related death in the United States by 2030. So far surgery remains the only curative option for pancreatic cancer, but fewer than 20% of patients have surgically resectable disease. Furthermore, pancreatic cancer exhibits a remarkable resistance to established therapeutic options, including chemotherapy, radiotherapy, and targeted therapy, because pancreatic cancer exhibits numerous mechanisms of resistance like genetic and epigenetic alterations and a complex and dense tumor microenvironment. The tumor microenvironment is populated with different types of immune cells that play a critical role in therapy resistance, tumor progression, and carcinogenesis. Cancer immunotherapy has now been recognized as the fourth pillar of cancer care and a number of preclinical and clinical studies have been conducted for pancreatic cancer. Targeting and modulating the tumor immune microenvironment could not only switch the immune system toward anti-cancer, but also may improve sensitivity toward established chemotherapy. In this review, we discuss both preclinical and clinical studies on pancreatic cancer immunotherapy with natural killer cells, dendritic cells, and chimeric antigen receptor T cells. Furthermore, we summarize strategies for reprogramming the tumor immune microenvironment by targeting macrophages and stromal cell factors in pancreatic cancer. The development of systemic therapies is essential for improving the outcomes of pancreatic cancer patients, and cancer immunotherapy would improve effectiveness of other established therapeutic options, which might together improve the prognosis of pancreatic tumors.