Article

CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans

Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Science (Impact Factor: 33.61). 03/2011; 331(6024):1612-6. DOI: 10.1126/science.1198443
Source: PubMed

ABSTRACT

Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma
(PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination
of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and
observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of
PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages
rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance
does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting
tumor stroma in the treatment of cancer.

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Available from: Babak Saboury
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    • "Combination therapeutic strategies that generate a treatment-permissive microenvironment hold much promise, as evidenced by current trials testing combinations of cytotoxic chemotherapy and microenvironmenttargeted agents such as PEGylated hyaluronidase (Provenzano et al. 2012;Jacobetz et al. 2013) to normalize the elevated pressure within the tumor microenvironment and relieve inhibition of intratumoral vasculature. Other agents are aimed at reducing immune-suppressive functions of stromal elements to overcome barriers to antitumor immunity, including strategies targeting tumorassociated macrophages (anti-CD40) (Beatty et al. 2011), vaccines to stimulate antitumor T-cell activation (Arensman et al. 2015;Le et al. 2015), or neutralizing antibodies against CXCL12/SDF-1, a stroma-derived chemokine that excludes T cells from the PDAC microenvironment (Feig et al. 2013). Increasing our understanding of the molecular mediators of tumor– stroma interaction will elucidate additional candidates to be targeted therapeutically. "
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    ABSTRACT: The basis of many human diseases arises from both genetic and epigenetic regulation. Recent advances in the understanding of the mechanisms underlying transcriptional and epigenetic regulation and their prevalence as contributors to a diverse range of human diseases have led us to focus on transcription and epigenetic changes in a variety of human disease conditions. Specifically, our recent studies in liver fibrosis and pancreatic cancer have demonstrated that the epigenetic regulation in hepatic stellate cells (HSCs) and pancreatic stellate cells (PSCs) significantly contributes to the progress in such diseases and presents great therapeutic potential. We show that the vitamin D receptor (VDR) acts as a master genomic suppressor in both HSC and PSC activation. The studies also have demonstrated that the VDR ligand reduces fibrosis and inflammation in a murine liver fibrosis and pancreatitis model. Although our current studies focus on characterizing the roles of VDR and regulatory regions within gene promoters and regulatory enhancers, we have expanded our effort to epigenetic mechanisms as major determinants of gene activation and repression in order to develop potential therapeutics to modulate stroma-associated pathologies including inflammation, fibrosis, and cancer.
    Full-text · Article · Jan 2016 · Cold Spring Harbor Symposia on Quantitative Biology
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    • "mice), with tumor regression being observed in 30% of mice. Interestingly, the activity of FGK45 in KPC mice did not appear to be dependent on the presence of T-cells or gemcitabine but did require macrophages, with CD40-activated macrophages being shown to rapidly infiltrate tumors where they transformed into tumoricidal cells, facilitating depletion of the tumor stroma [29]. "
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    ABSTRACT: Ever since a pivotal study in 1997 demonstrated superiority of gemcitabine over 5-FU, gemcitabine monotherapy has, until recently, comprised the standard of care in patients with advanced pancreatic cancer. However, the emerging recognition of the pancreatic cancer microenvironment, including the particularly abundant stroma, as playing a key role in disease progression and resistance to chemotherapy has marked somewhat of a paradigm shift in the way treatment of advanced pancreatic cancer is viewed, with these very same biological defenses conversely offering an Achilles heel with which to combat this aggressive disease. Recently, this approach was validated for the first time in a pivotal phase III trial in which patients received nab-paclitaxel, a stroma-targeted drug, with gemcitabine. Overall survival was significantly (p<0.001) prolonged in the combination arm, compared with gemcitabine alone, and thus these convincing results pave the way forward for future treatment regimens that employ a multipronged approach, targeting not only the primary tumor but the surrounding microenvironment as well.
    Full-text · Article · Oct 2014 · Cancer Treatment Reviews
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    • "Recently, it has become clear that there is probably not one single compound that can achieve this goal [22]. A proposed strategy therefore is a combination of infusion of antibodies against CD40 in order to stimulate the secondary lymph node resident macrophages to migrate into the tumor tissue with IFN-γ to effectively reprogram tumor-induced M2-like macrophages into activated IL-12 producing M1 cells [41]. In addition, targeting the nuclear factor κB (NF-κB) signaling pathway, a crucial pathway in the activation of M2 TAMs, was shown to switch M2 TAMs to a M1 phenotype [42]. "
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    ABSTRACT: Hypothesis The tumor micro-environment and especially the different macrophage phenotypes appear to be of great influence on the behavior of multiple tumor types. M1 skewed macrophages possess anti-tumoral capacities, while the M2 polarized macrophages have pro-tumoral capacities. We analyzed if the macrophage count and the M2 to total macrophage ratio is a discriminative marker for outcome after surgery in malignant pleural mesothelioma (MPM) and studied the prognostic value of these immunological cells. Methods 8 MPM patients who received induction chemotherapy and surgical treatment were matched on age, sex, tumor histology, TNM stage and EORTC score with 8 patients who received chemotherapy only. CD8 positive T-cells and the total macrophage count, using the CD68 pan-macrophage marker, and CD163 positive M2 macrophage count were determined in tumor specimens prior to treatment. Results The number of CD68 and CD163 cells was comparable between the surgery and the non-surgery group, and was not related to overall survival (OS) in both the surgery and non-surgery group. However, the CD163/CD68 ratio did correlate with OS in both in the total patient group (Pearson r −0.72, p<0.05). No correlation between the number of CD8 cells and prognosis was found. Conclusions The total number of macrophages in tumor tissue did not correlate with OS in both groups, however, the CD163/CD68 ratio correlates with OS in the total patient group. Our data revealed that the CD163/CD68 ratio is a potential prognostic marker in epithelioid mesothelioma patients independent of treatment but cannot be used as a predictive marker for outcome after surgery.
    Full-text · Article · Sep 2014 · PLoS ONE
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