Pancreatic Ductal Adenocarcinoma Immunotherapy Research Articles

High hypoxia status in pancreatic cancer is associated with multiple hallmarks of an immunosuppressive tumor microenvironment.

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is a particularly lethal disease that is often diagnosed late and is refractory to most forms of treatment. Tumour hypoxia is a key hallmark of PDAC and is purported to contribute to multiple facets of disease progression such as treatment resistance, increased invasiveness, metabolic reprogramming, and immunosuppression. We used the Buffa gene signature as a hypoxia score to profile transcriptomics datasets from PDAC cases. We performed cell-type deconvolution and gene expression profiling approaches to compare the immunological phenotypes of cases with low and high hypoxia scores. We further supported our findings by qPCR analyses in PDAC cell lines cultured in hypoxic conditions. First, we demonstrated that this hypoxia score is associated with increased tumour grade and reduced survival suggesting that this score is correlated to disease progression. Subsequently, we compared the immune phenotypes of cases with high versus low hypoxia score expression (HypoxiaHI vs. HypoxiaLOW) to show that high hypoxia is associated with reduced levels of T cells, NK cells and dendritic cells (DC), including the crucial cDC1 subset. Concomitantly, immune-related gene expression profiling revealed that compared to HypoxiaLOW tumours, mRNA levels for multiple immunosuppressive molecules were notably elevated in HypoxiaHI cases. Using a Random Forest machine learning approach for variable selection, we identified LGALS3 (Galectin-3) as the top gene associated with high hypoxia status and confirmed its expression in hypoxic PDAC cell lines. In summary, we demonstrated novel associations between hypoxia and multiple immunosuppressive mediators in PDAC, highlighting avenues for improving PDAC immunotherapy by targeting these immune molecules in combination with hypoxia-targeted drugs.

SNHG17 alters anaerobic glycolysis by resetting phosphorylation modification of PGK1 to foster pro-tumor macrophage formation in pancreatic ductal adenocarcinoma

BackgroundWithin the tumor immune microenvironment (TME), tumor-associated macrophages (TAMs) are crucial in modulating polarization states to influence cancer development through metabolic reprogramming. While long non-coding RNAs (lncRNAs) have been shown to play a pivotal role in the progression of various cancers, the underlying mechanisms by which lncRNAs alter M2 polarization through macrophage metabolism remodeling remain unelucidated.MethodsRNA sequencing was used to screen for differentially expressed lncRNAs in TAMs and normal tissue-resident macrophages (NTRMs) isolated from pancreatic ductal adenocarcinoma (PDAC) tissues, whilst RT-qPCR and FISH were employed to detect the expression level of SNHG17. Moreover, a series of in vivo and in vitro experiments were conducted to assess the functions of SNHG17 from TAMs in the polarization and glycolysis of M2-like macrophages and in the proliferation and metastasis of pancreatic cancer cells (PCs). Furthermore, Western blotting, RNA pull-down, mass spectrometry, RIP, and dual-luciferase assays were utilized to explore the underlying mechanism through which SNHG17 induces pro-tumor macrophage formation.ResultsSNHG17 was substantially enriched in TAMs and was positively correlated with a worse prognosis in PDAC. Meanwhile, functional assays determined that SNHG17 promoted the malignant progression of PCs by enhancing M2 macrophage polarization and anaerobic glycolysis. Mechanistically, SNHG17 could sponge miR-628-5p to release PGK1 mRNA and concurrently interact with the PGK1 protein, activating the pro-tumorigenic function of PGK1 by enhancing phosphorylation at the T168A site of PGK1 through ERK1/2 recruitment. Lastly, SNHG17 knockdown could reverse the polarization status of macrophages in PDAC.ConclusionsThe present study illustrated the essential role of SNHG17 and its molecular mechanism in TAMs derived from PDAC, indicating that SNHG17 might be a viable target for PDAC immunotherapy.

Donor T Cell Infusions Limit Novel Immune Checkpoint Therapy in Pancreatic Cancer: Implications for Adoptive T Cell Therapy

Background: We have previously published that pancreatic cancers over-express an immunosuppressive peptide, vasoactive intestinal polypeptide (VIP), and that a novel combination of antin-PD1 antibodies and small molecule antagonists to the VIP receptor can induce complete remission of pancreatic ductal adenocarcinoma (PDAC) in multiple mouse models (Ravibndranathan, Nat. Comm. 2022). To enhance the efficacy of this novel immunotherapy approach, we hypothesized that infusions of additional donor T cells to PDAC-bearing mice receiving the combination of anti-PD1/VIP receptor antagonists would lead to more intra-tumoral effector T cells and increased tumor regression rates. To investigate the potential impact of adoptive splenocyte infusion on checkpoint immunotherapy, we established sub-cutaneous KPC PDAC tumors in C57Bl/6 mice. As previously described, we treated them with a combination of ANT308 (VIP-receptor antagonists) and anti-PD1. We tested whether adding splenocyte infusions from donor mice that were immunologically naïve or donor mice previously engrafted with PDAC with regressed (positive control) or progressed tumors (negative control) would enhance the efficacy of the immune checkpoint blockade therapy. Methods: C57BL/6 B6 CD45.1 recipient mice were inoculated subcutaneously with 1 x 10 6 KPC-luc PDAC cell line cells on day -5. Recipient mice received anti-PD1 (200mg) every three days (totaling four doses) and 21 daily s.c. injections of 20 ug ANT308. Splenocytes from three groups of CD45.2+ C57BL/6 donor mice were injected into tumor-bearing recipients: naive mice, mice with a history of KPC regression post-ANT308/anti-PD1 treatment, and mice with progressed KPC tumors without any treatment. Anti-PD1 and ANT308 treatments were initiated simultaneously with adoptive splenocyte infusion (25 x 10 6 cells) on day 0. Tumor size was measured biweekly, and IVIS imaging was performed weekly. Blood was drawn weekly from recipient mice for flow cytometric analysis of immune cell subsets. A fraction of tumor-bearing recipient mice was euthanized ten days after donor splenocyte infusion and initiation of immune checkpoint therapy or at IAUCAC-defined endpoints. When tumor-bearing mice were euthanized, the spleen, lymph nodes, and tumors were harvested for further flow cytometric analysis. The remaining mice were monitored for tumor growth and survival kinetics. Results: Contrary to our original hypothesis, we observed substantially lower survival rates and faster tumor growth in the group that received splenocytes from immunologically naive donor mice versus the group treated with splenocytes from tumor-bearing mice (Figures 1A and 1B). Splenocytes from immunologically naive donors contained fewer Treg cells, whereas myeloid-derived suppressor cells (CD11b+Ly-6G+ Gr-1+) were increased in donor splenocytes from tumor-bearing mice. We next repeated the experiment utilizing the adoptive transfer of splenocytes from immunologically naïve donors separated into 8 x 10 6 MACS-purified T cell or 17 x 10 6 non-T cell fractions. Remarkably, the transfer of 8 x 10 6 immunologically naïve T cells abrogated the efficacy of immune checkpoint therapy leading to rapid tumor growth compared to tumor regression in mice treated with immune checkpoint therapy without added donor splenocytes or mice that received immune checkpoint therapy with 17 x 10 6 T-cell-depleted donor splenocytes. Flow cytometric and gene expression analyses of splenocytes from the recipient mice, and those not receiving donor T cell infusions, revealed that the tetramer population in the infusion group was significantly higher than in the group treated only with immune checkpoint inhibitors. Conclusion: Our findings indicated that natural suppressor/ Treg in immunologically naïve splenocytes could exert a profound negative regulatory effect on immune checkpoint therapy's efficacy in a murine PDAC model. Despite having fewer Treg than splenocytes from tumor-bearing donors, immunologically naïve natural Treg had increased potency in suppressing anti-cancer immunity. These findings suggest the importance of the depletion of natural Treg in adoptive cell therapy strategies to treat solid tumor malignancies. This research underscores the critical role of immune contexture in shaping therapeutic outcomes and proposes a novel biomarker for patient stratification in PDAC immunotherapy.

Self-Adaptive Nanoregulator to Mitigate Dynamic Immune Evasion of Pancreatic Cancer.

The advance of immunotherapy has shifted the paradigm of cancer management in clinics. Nevertheless, a considerable subset of pancreatic ductal adenocarcinoma (PDAC) patients marginally respond to current immunotherapy due to the occurrence of dynamic immune evasion arising from intrinsic and therapeutic stress. In this investigation, the pivotal role of pancreatic cancer-associated fibroblast (CAF)-induced fibrosis and tumor cell-mediated T-cell exhaustion in driving the dynamic immune evasion is identified. Building upon this discovery, the authors herein engineer a novel peptide-drug conjugate (PDC)-based self-adaptive nanoregulator for mitigating dynamic immune evasion of PDAC. The resulting nanoregulator can perform a two-stage morphology transformation from spherical micelle to nanofiber, and subsequently from nanofiber to spherical nanoparticles. Such kind of nanostructure design can facilitate differentialized delivery of CAF inhibitor in the extracellular matrix for intervening CAF-mediated tumor fibrosis, and indoleamine 2,3-dioxygenase 1 inhibitor to tumor cells for relieving IDO1-kynurenine axis-induced T-cell exhaustion. Antitumor study with the self-adaptive nanoregulator elicited persistent antitumor immunity and remarkable antitumor performance in both Panc02 and KPC tumor models in vivo. Taken together, the PDC-based self-adaptive nanoregulator may provide a novel avenue for enhanced PDAC immunotherapy.

Receptor-interacting Protein Kinase 2 Is an Immunotherapy Target in Pancreatic Cancer.

PDAC is resistant to almost all available therapies, including immune checkpoint blockade. Through in vivo CRISPR screen, we identified that RIPK2 plays a crucial role in facilitating immune evasion by impeding antigen presentation and cytotoxic T-cell killing. Targeting tumor-intrinsic RIPK2 either genetically or pharmacologically improves PDAC to anti-PD-1 immunotherapy. See related commentary by Liu et al., p. 208 . This article is featured in Selected Articles from This Issue, p. 201.

Pancreatic Ductal Adenocarcinoma: Current and Emerging Treatments

Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease with increasing incidence and mortality rates. The most effective treatment for Pancreatic Ductal Adenocarcinoma is surgery, but because of the late-stage diagnosis which is typical among PDAC patients, as well as poor imaging technology, surgery is not a viable option for 80-85% of patients. Therefore, the most common treatments for PDAC currently are Chemotherapy, Immunotherapy, and Radiotherapy. Chemotherapy for PDAC is performed with a combination of drugs. The current standards of chemotherapy drug combinations are being challenged and new chemotherapy combinations are under clinical trial. Immunotherapy for PDAC consists of immunomodulators, oncolytic viruses, adoptive cell therapies, and cancer vaccines. Recently, a shift of focus within PDAC immunotherapy research has yielded an emphasis on protein inhibition. A new protein inhibition strategy is under clinical trial. Radiotherapy is rarely used to treat PDAC in recent years, but there is an emerging hypothesis implying that radiotherapy may be used on tumors to kill tissue that may not be removed via surgery. The future of PDAC treatment is unpredictable - because of the high mortality rate and low survival rate relative to other cancers, researchers are forced to think creatively and pursue treatments different than those of other cancers. The likelihood of improvement in PDAC treatment is great because of the current poor standard and the vast amount of emerging research.

Engineered TCR T-cell therapy targeting mass spectrometry-identified natural epitope in PDAC

Tumor antigens are crucial targets for T-cell-based therapy to induce tumor-specific rejection. However, identifying pancreatic ductal adenocarcinoma (PDAC)-specific T-cell epitopes has been challenging. Using advanced mass spectrometry (MS) analysis, we previously identified cancer-associated, class I MHC-bound epitopes shared by multiple PDAC patients with different HLA-A types. Here, we investigated one of these epitopes, LAMC2203-211, a naturally occurring nonmutated epitope on the LAMC2 protein. Following stimulation with the LAMC2203-211 peptide, we cloned T-cell receptors (TCRs) and transduced them into the Jurkat human T-cell line using a lentiviral vector. We found that Jurkat cells expressing LAMC2203-211-specific TCRs resulted in potent, LAMC2 specific, in vitro cytotoxic effects on PDAC cells. Furthermore, in mice that harbored either subcutaneously or orthotopically implanted tumors originating from both HLA-A allele-matched and unmatched PDAC patients, tumor growth was suppressed in a LAMC2-dependent manner following the infusion of LAMC2-targeting T cells. We have therefore developed a LAMC2-specific TCR-based T-cell therapy strategy likely suitable for many PDAC patients. This is the first study to adopt MS analysis to identify natural CD8+ T-cell epitopes in PDAC that could potentially serve as targets for PDAC immunotherapy.

Neoadjuvant Immunotherapy for Localized Pancreatic Cancer: Challenges and Early Results.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease due to its late presentation and tendency to recur early even after optimal surgical resection. Currently, there are limited options for effective systemic therapy. In addition, PDAC typically generates an immune-suppressive tumor microenvironment; trials of immunotherapy in metastatic PDAC have yielded disappointing results. There is considerable interest in using immunotherapy approaches in the neoadjuvant setting in order to prime the immune system to detect and prevent micrometastatic disease and recurrence. A scoping review was conducted to identify published and ongoing trials utilizing preoperative immunotherapy. In total, 9 published trials and 27 ongoing trials were identified. The published trials included neoadjuvant immune checkpoint inhibitors, cancer vaccines, and other immune-modulating agents that target mechanisms distinct from that of immune checkpoint inhibition. Most of these are early phase trials which suggest improvements in disease-free and overall survival when combined with standard neoadjuvant therapy. Ongoing trials are exploring various combinations of these agents with each other and with chemotherapy and/or radiation. Rational combination immunotherapy in addition to standard neoadjuvant therapy has the potential to improve outcomes in PDAC, but further clinical trials are needed, particularly those which utilize an adaptive trial design.

The clinical terrain of immunotherapies in heterogeneous pancreatic cancer: unravelling challenges and opportunities.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer and has abysmal survival rates. In the past two decades, immunotherapeutic agents with success in other cancer types have gradually been trialled against PDACs at different stages of cancer progression, either as a monotherapy or in combination with chemotherapy. Unfortunately, to this day, chemotherapy still prolongs the survival rates the most and is prescribed in clinics despite the severe side effects in other cancer types. The low success rates of immunotherapy against PDAC have been attributed most frequently to its complex and multi-faceted tumour microenvironment (TME) and low mutational burden. In this review, we give a comprehensive overview of the immunotherapies tested in PDAC clinical trials thus far, their limitations, and potential explanations for their failure. We also discuss the existing classification of heterogenous PDACs into cancer, cancer-associated fibroblast, and immune subtypes and their potential opportunity in patient selection as a form of personalisation of PDAC immunotherapy. © 2023 The Pathological Society of Great Britain and Ireland.

Targeting leucine-rich repeat serine/threonine-protein kinase 2 sensitizes pancreatic ductal adenocarcinoma to anti-PD-L1 immunotherapy

Immune checkpoints blockade therapy is not sensitive in pancreatic ductal adenocarcinoma (PDAC) and negative feedback of tumor immune evasion might take part of responsibility. We isolated CD8+ T cells and cultured in vitro. Proteomic analysis was performed to compare changes of Panc02 cell lines cultured with conditional medium and leucine rich repeat kinase 2 (LRRK2) was identified as a differential gene. LRRK2 expression was related to CD8+ T cells spatial distribution in PDAC clinical samples and was upregulated by CD8+ T cells via interferon gamma (IFN-γ) simulation in vitro. Knocking down or pharmacologically inhibition of LRRK2 activated anti-pancreatic cancer immune response in mice which meant that LRRK2 acted as an immunosuppressive gene. Mechanically, LRRK2 phosphorylated PD-L1 at T210 to inhibit its ubiquitination-mediated proteasomal degradation. LRRK2 inhibition attenuated PD-1/PD-L1 blockade-mediated, T cell-induced, upregulation of LRRK2/PD-L1, thus sensitizing anti-PD therapy. In addition, Adenosylcobalamin, the activated form of Vitamin B12, which was found as a broad-spectrum inhibitor of LRRK2, could inhibited LRRK2 in vivo and sensitize immunotherapy in PDAC as well, which endowed LRRK2 inhibition a potential clinical translational value. Therefore, PD-L1 blockade combined with LRRK2 inhibition could be a novel therapy strategy for PDAC.

Comprehensive analysis and identification of prognostic biomarkers and immunotherapeutic targets in the NADPH oxidase family (and its regulatory subunits) in pancreatic ductal adenocarcinoma.

This study aimed to evaluate the role of NADPH in pancreatic ductal adenocarcinoma using bioinformatic analyses and experimental validations. We compared the expression levels, performed GO and KEGG analysis of NADPH oxidase family and its regulatory subunits, and determined the survival of patients with pancreatic ductal adenocarcinoma by GEPIA, David and KM plotter. The relationship between their expression with immune infiltration levels, phagocytotic/NK cell immune checkpoints, recruitment-related molecules were detected by Timer 2.0 and TISIDB, respectively. Subsequently, their correlation with NK cell infiltration level was verified by immunohistochemistry. The expression of some members of the NADPH oxidase family and its regulatory subunits was significantly increased in pancreatic ductal adenocarcinoma tissues compared to that in normal tissues and was positively correlated with natural killer (NK) cell infiltration. Furthermore, the NADPH oxidase family and its regulatory subunits were associated with survival and immune status in patients with pancreatic ductal adenocarcinoma, including chemokines, immune checkpoints, and immune infiltration levels of NK cells, monocytes, and myeloid-derived suppressor cells. These results suggest the NADPH oxidase family and its regulatory subunits might serve as indicators for predicting the responsiveness to immunotherapy and outcome of patients with pancreatic ductal adenocarcinoma, providing a new perspective or strategy for immunotherapy in pancreatic ductal adenocarcinoma.

METTL3 suppresses pancreatic ductal adenocarcinoma progression through activating endogenous dsRNA-induced anti-tumor immunity.

Although immunotherapy improves clinical outcomes in several types of malignancies, as an immunologically 'cold' tumor, pancreatic ductal adenocarcinoma (PDAC) is arrantly resistant to immunotherapy. However, the role of N6-methyladenosine (m6A) modification in the immune microenvironment of PDAC is still poorly understood. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify differentially expressed m6A related enzymes. The biological role and mechanism of METTL3 in PDAC growth and metastasis were determined in vitro and in vivo. RNA-sequencing and bioinformatics analysis were used to identify signaling pathways involved in METTL3. Western blot, m6A dot blot assays, co-immunoprecipitation, immunofluorescence, and flow cytometry were used to explore the molecular mechanism. Here, we demonstrate that METTL3, the key regulator of m6A modification, is downregulated in PDAC, and negatively correlates with PDAC malignant features. Elevated METTL3 suppresses PDAC growth and overcomes resistance to immune checkpoint blockade. Mechanistically, METTL3 promotes the accumulation of endogenous double-stranded RNA (dsRNA) through protecting m6A-transcripts from further Adenosine-to-inosine (A-to-I) editing. The dsRNA stress activates RIG-I-like receptors (RLRs) to enhance anti-tumor immunity, finally suppressing PDAC progression. Our findings indicate that tumor cell-intrinsic m6A modification participates in the regulation of tumor immune landscape. Adjusting the m6A level may be an effective strategy to overcome the resistance to immunotherapy and increase responsiveness to immunotherapy in PDAC.

M6A-Related Long Non-Coding RNA Displays Utility in Predicting Prognosis, Portraying the Tumor Immune Microenvironment and Guiding Immunotherapy in Pancreatic Ductal Adenocarcinoma.

N6-methyladenosine (m6A) lncRNA plays a pivotal role in cancer. However, little is known about its role in pancreatic ductal adenocarcinoma (PDAC) and its tumor immune microenvironment (TIME). Based on The Cancer Genome Atlas (TCGA) cohort, m6A-related lncRNAs (m6A-lncRNA) with prognostic value were filtered using Pearson analysis and univariate Cox regression analysis. Distinct m6A-lncRNA subtypes were divided using unsupervised consensus clustering. Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to establish an m6A-lncRNA-based risk score signature. The CIBERSORT and ESTIMATE algorithms were employed to analyze the TIME. The expression pattern of TRAF3IP2-AS1 was examined using qRT-PCR. The influence of TRAF3IP2-AS1 knockdown on cell proliferation was estimated by performing CCK8, EdU and colony-formation assays. Flow cytometry was applied to measure the effect of TRAF3IP2-AS1 knockdown on cell cycle and apoptosis. The in vivo anti-tumor effect of TRAF3IP2-AS1 was validated in a tumor-bearing mouse model. Two m6A-lncRNA subtypes with different TIME features were clarified. A risk score signature was constructed as a prognostic predictor based on m6A-lncRNAs. The risk score also correlated with TIME characterization, which facilitated immunotherapy. Finally, the m6A-lncRNA TRAF3IP2-AS1 was proved to be a tumor suppressor in PDAC. We comprehensively demonstrated m6A-lncRNAs to be useful tools for prognosis prediction, TIME depiction and immunotherapeutic guidance in PDAC.

PLA2G2A+ cancer-associated fibroblasts mediate pancreatic cancer immune escape via impeding antitumor immune response of CD8+ cytotoxic T cells

Our previous research defined a novel metabolic cancer associated fibroblasts subset (meCAFs) enriched in loose-type pancreatic ductal adenocarcinoma (PDAC) and related to CD8+ T cells accumulation. Consistently, the abundance of meCAFs was associated with poor prognosis but better immunotherapy responses in PDAC patients. However, the metabolic characteristic of meCAFs and its cross-talk with CD8+ T cells remain to be elucidated. In this study, we identified PLA2G2A as a marker of meCAFs. In particular, the abundance of PLA2G2A+ meCAFs was positively related to the accumulation of total CD8+ T cells and negatively correlated with clinical outcomes of PDAC patients and infiltration of intratumoral CD8+ T cells. We demonstrated that PLA2G2A+ meCAFs substantially attenuated the antitumor ability of tumor infiltrating CD8+ T cells and facilitated tumor immune escape in PDAC. Mechanistically, PLA2G2A regulated the function of CD8+ T cells as a pivotal soluble mediator via MAPK/Erk and NF-κB signaling pathways. In conclusion, our study identified the unrecognized role of PLA2G2A+ meCAFs in promoting tumor immune escape by impeding the antitumor immune function of CD8+ T cells, and strongly suggested PLA2G2A as a promising biomarker and therapeutic target for immunotherapy in PDAC.

A pilot study of gut microbiome modulation to enable efficacy of neoadjuvant checkpoint-based immunotherapy (IO) following chemotherapy in pancreatic ductal adenocarcinoma (PDAC).

TPS759 Background: Neoadjuvant therapy is now a standard strategy for localized PDAC, and this preoperative window provides an excellent opportunity in which to test novel therapeutic approaches. Trials using IO in PDAC have largely been unsuccessful, and immune tolerance is implicated as a major mechanism of IO resistance. The gut and tumor microbiome have emerged as key modulators of response to both IO and chemotherapy. High tumor microbial diversity has been linked to longer survival in PDAC, and gut microbiota may have the ability to colonize pancreatic tumors. There is preclinical evidence that endogenous microbiota promotes the immunosuppressive tumor microenvironment characteristic of PDAC through stimulation of pro-tumor regulatory T cells and myeloid-derived suppressor cells at the expense of anti-tumor activated CD4+ and CD8+ T cells. Further, preclinical data show that ablation of the gut microbiota may induce T cell activation, improve immune surveillance, and increase sensitivity to IO. We hypothesize that ablative antibiotics (abx) will activate tumor infiltrating T cells and enhance IO activity in PDAC. Methods: This is a multi-center, single-arm, open-label pilot study of pre-operative chemotherapy followed by abx and pembrolizumab to evaluate overall immune response to abx + IO. Eligible patients will have histologically confirmed, resectable PDAC, without probiotic consumption or use of immunosuppressive agents. Patients will be enrolled at diagnosis after undergoing a baseline biopsy. They will then receive mFOLFIRINOX every 2 weeks for 5 cycles. After completion of chemotherapy, ciprofloxacin 500 mg PO BID and metronidazole 500 mg PO TID will be administered for 21 days, and pembrolizumab 200 mg IV x1 will be given 7 days after initiation of abx. Patients will then undergo surgical resection and adjuvant therapy at the investigators’ discretion. On-treatment biopsy will be obtained prior to cycle 5 of mFOLFIRINOX. Blood and stool will be collected at baseline, during mFOLFIRINOX therapy, before and after pembrolizumab administration, and postoperatively. The primary endpoint is the overall immune response, which will be measured as activation of one or more of the T cell markers HLA-DR, CD38, CD25, Ki67, and CD69, defined as an increase in expression level of at least 20% from the on-treatment specimen to the surgical specimen, before and after abx + IO. Key secondary endpoints will be the evaluation of adverse events, R0 resection rate, histologic regression score, objective response rate, and overall survival rate. Correlative studies will be carried out to evaluate immune and microbiome changes in the blood and tissue following abx and pembrolizumab. These findings will be correlated with clinical endpoints. The target study accrual is 25 patients. Clinical trial information: NCT05462496 .

A rare case of sporadic mismatch repair deficient pancreatic ductal adenocarcinoma that responded to ipilimumab and nivolumab combination treatment: case report.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a poor prognosis. Despite high efficacy in multiple cancers, immunotherapy has had very little success in treating PDAC due to unfavorable characteristics such as low tumor mutational burden (TMB), low microsatellite instability (MSI), and non-immunogenic tumor microenvironment. Recently, however, there have been reports of rare PDAC cases with high TMB and DNA mismatch repair deficiency (dMMR) that have demonstrated positive response to immunotherapy. All these cases have also presented with Lynch Syndrome, or germline mutations in MMR genes. Here, we report a 57-year-old male with stage IV PDAC whose tumor profile revealed high TMB, high MSI, and dMMR, but no germline mutations in genes associated with hereditary cancers including those associated with Lynch Syndrome. After a series of ineffective treatments, the patient showed positive response to combined ipilimumab and nivolumab immunotherapy. To our knowledge, this is the first report of an advanced PDAC case with sporadic dMMR, high TMB, and no Lynch Syndrome having a good response to immunotherapy. This case further supports TMB and high MSI/dMMR being possible biomarkers for immunotherapy of PDAC as well as highlights the importance of both germline and somatic testing of patients with PDAC.

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

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is characterized by poor treatment response and low survival time. The current clinical treatment for advanced PDAC is still not effective. In recent years, the research and application of immunotherapy have developed rapidly and achieved substantial results in many malignant tumors. However, the translational application in PDAC is still far from satisfactory and needs to be developed urgently. To carry out the study of immunotherapy, it is necessary to fully decipher the immune characteristics of PDAC. This review summarizes the recent progress of the tumor microenvironment (TME) of PDAC and highlights its link with immunotherapy. We describe the molecular cues and corresponding intervention methods, collate several promising targets and progress worthy of further study, and put forward the importance of integrated immunotherapy to provide ideas for future research of TME and immunotherapy of PDAC.

BNIP3 enhances pancreatic cancer cell migration and proliferation via modulating autophagy under hypoxia

Chemotherapy and immunotherapy for pancreatic ductal adenocarcinoma (PDAC) have limited success for the intricated surrounding cancer microenvironment. Hypoxic microenvironment in PDAC causes the activation of multiple different molecules and signaling pathways compared with normoxia. We studied the roles of BNIP3 for the migration and proliferation of PDAC and Panc1 cells in vitro. In the present study, we found that BNIP3 expression was elevated and enhanced the migration and proliferation of CFPAC-1 and Panc1 cells under hypoxia. The upregulation of BNIP3 was important for the autophagic activation, while inhibition of autophagy with siRNA targeting Atg5 and Atg7 impaired the hypoxia-induced cell migration and proliferation. Additionally, blocking ERK1/2 mitogen-activated protein kinase (MAPK) signaling with PD98058 significantly down-regulated BNIP3 expression, autophagic activation, as well as the migration and proliferation of CFPAC-1 and Panc1 cells under hypoxia. Collectively, our results here uncover a hitherto unknown hypoxia-BNIP3-autophagy axis in modulating the migration and proliferation and provide a potential intriguing drug target for the therapy of PDAC.

Nanoparticle-Based Therapeutic Strategies for Enhanced Pancreatic Ductal Adenocarcinoma Immunotherapy.

Immunotherapy has dramatically changed prognosis for patients with malignant tumors. However, as a non-immunogenic tumor, pancreatic ductal adenocarcinoma (PDAC) has a low response to immunotherapy. Factors that contribute to the inefficiency of PDAC immunotherapy include the tumor microenvironment (TME) and its dense stroma, which acts as a barrier for drug delivery and immune cell infiltration. Recent studies have shown that nanoparticle-based therapeutic strategies have more promising applications in improving drug delivery and reversing the immunosuppressive TME for PDAC. Therefore, nanomaterial-based therapeutic approaches are expected to enhance the effectiveness of immunotherapy and improve prognosis of patients with PDAC. Here, we outline the status and dilemma of PDAC immunotherapy, and summarize the latest advances in nanoparticle-based treatment strategies to enhance the efficacy of PDAC immunotherapy.

The Role of the Microbiome in Pancreatic Cancer.

Simple SummaryPancreatic cancer is deadly cancer characterized by dense stroma creating an immunosuppressive tumor microenvironment. Accumulating evidences indicate that the microbiome plays an important role in pancreatic cancer development and progression via the local and systemic inflammation and immune responses. The alteration of the microbiome modulates the tumor microenvironment and immune system in pancreatic cancer, which affects the efficacy of chemotherapies including immune-targeted therapies. Understanding the role of microbiome and underlying mechanisms may lead to novel biomarkers and therapeutic strategies for pancreatic cancer. This review summarizes the current evidence on the role of the microbiome in pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with little improvement in outcomes in recent decades, although the molecular and phenotypic characterization of PDAC has contributed to advances in tailored therapies. PDAC is characterized by dense stroma surrounding tumor cells, which limits the efficacy of treatment due to the creation of a physical barrier and immunosuppressive environment. Emerging evidence regarding the microbiome in PDAC implies its potential role in the initiation and progression of PDAC. However, the underlying mechanisms of how the microbiome affects the local tumor microenvironment (TME) as well as the systemic immune system have not been elucidated in PDAC. In addition, therapeutic strategies based on the microbiome have not been established. In this review, we summarize the current evidence regarding the role of the microbiome in the development of PDAC and discuss a possible role for the microbiome in the early detection of PDAC in relation to premalignant pancreatic diseases, such as chronic pancreatitis and intraductal papillary mucinous neoplasm (IPMN). In addition, we discuss the potential role of the microbiome in the treatment of PDAC, especially in immunotherapy, although the biomarkers used to predict the efficacy of immunotherapy in PDAC are still unknown. A comprehensive understanding of tumor-associated immune responses, including those involving the microbiome, holds promise for new treatments in PDAC.