SUMMARY
The contributions of the innate immune system to the development of pancreatic cancer are still ill-defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (ADM), which then give rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. We here demonstrate presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively-activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors such as IL-1ra and CCL2 to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly-decreased the accumulation of alternatively-activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.
During development of pancreatic cancer, alternatively activated macrophages contribute to fibrogenesis, pancreatic intraepithelial neoplasia (PanIN) lesion growth, and generation of an immunosuppressive environment. Here, we show that the immunomodulatory agent pomalidomide depletes pancreatic lesion areas of alternatively activated macrophage populations. Pomalidomide treatment resulted in downregulation of interferon regulatory factor 4, a transcription factor for M2 macrophage polarization. Pomalidomide-induced absence of alternatively activated macrophages led to a decrease in fibrosis at PanIN lesions and in syngeneic tumors; this was due to generation of an inflammatory, immune-responsive environment with increased expression of IL1a and presence of activated (IFNg-positive) CD4 þ and CD8 þ T-cell populations. Our results indicate that pomalidomide could be used to decrease fibrogenesis in pancreatic cancer and may be ideal as a combination treatment with chemotherapeutic drugs or other immunotherapies. Significance: These findings reveal new insights into how macrophage populations within the pancreatic cancer microenvironment can be modulated, providing the means to turn the microenvironment from immunosuppressive to immuneresponsive.
Pancreatitis is an inflammatory disease of the pancreas characterized by dysregulated activity of digestive enzymes, necrosis, immune infiltration, and pain. Repeated incidence of pancreatitis is an important risk factor for pancreatic cancer. Legumain, a lysosomal cysteine protease, has been linked to inflammatory diseases such as atherosclerosis, stroke, and cancer. Until now, legumain activation has not been studied during pancreatitis. We used a fluorescently quenched activity-based probe to assess legumain activation during caerulein-induced pancreatitis in mice. We detected activated legumain by ex vivo imaging, confocal microscopy, and gel electrophoresis. Compared with healthy controls, legumain activity in the pancreas of caerulein-treated mice was increased in a time-dependent manner. Legumain was localized to CD68(+) macrophages and was not active in pancreatic acinar cells. Using a small-molecule inhibitor of legumain, we found that this protease is not essential for the initiation of pancreatitis. However, it may serve as a biomarker of disease, since patients with chronic pancreatitis show strongly increased legumain expression in macrophages. Moreover, the occurrence of legumain-expressing macrophages in regions of acinar-to-ductal metaplasia suggests that this protease may influence reprogramming events that lead to inflammation-induced pancreatic cancer.
Protein Kinase C isoforms have been implicated in regulating multiple processes within the healthy pancreas. Moreover, their dysregulation contributes to all aspects of pancreatic disease. In this review, with a focus on acinar, ductal, and islet cells, we highlight the roles and contributions of the different PKC isoforms to normal pancreas function. We also discuss the contribution of PKC enzymes to pancreatic diseases, including insulin resistance and diabetes mellitus, as well as pancreatitis and the development and progression of pancreatic cancer.
<p>Supplementary Table 1: Table with antibodies and dilutions used Supplementary Figure S1: Treatment scheme and analyses of stroma Supplementary Figure S2: Additional analyses of cell death and cell proliferation Supplementary Figure S3: Presence of Ym1+ macrophage and IL-13 in PanIN areas Supplementary Figure S4: Additional data on the role of IRF4 in macrophage polarization Supplementary Figure S5: Presence of macrophage-secreted factors and T cells Supplementary Figure S6: Treatment scheme and analyses of presence of immune cells Supplementary Figure S7: Blood counts and coagulation profile</p>
<p>Supplementary Table 1: Table with antibodies and dilutions used Supplementary Figure S1: Treatment scheme and analyses of stroma Supplementary Figure S2: Additional analyses of cell death and cell proliferation Supplementary Figure S3: Presence of Ym1+ macrophage and IL-13 in PanIN areas Supplementary Figure S4: Additional data on the role of IRF4 in macrophage polarization Supplementary Figure S5: Presence of macrophage-secreted factors and T cells Supplementary Figure S6: Treatment scheme and analyses of presence of immune cells Supplementary Figure S7: Blood counts and coagulation profile</p>
<div>Abstract<p>During development of pancreatic cancer, alternatively activated macrophages contribute to fibrogenesis, pancreatic intraepithelial neoplasia (PanIN) lesion growth, and generation of an immunosuppressive environment. Here, we show that the immunomodulatory agent pomalidomide depletes pancreatic lesion areas of alternatively activated macrophage populations. Pomalidomide treatment resulted in downregulation of interferon regulatory factor 4, a transcription factor for M2 macrophage polarization. Pomalidomide-induced absence of alternatively activated macrophages led to a decrease in fibrosis at PanIN lesions and in syngeneic tumors; this was due to generation of an inflammatory, immune-responsive environment with increased expression of IL1α and presence of activated (IFNγ-positive) CD4<sup>+</sup> and CD8<sup>+</sup> T-cell populations. Our results indicate that pomalidomide could be used to decrease fibrogenesis in pancreatic cancer and may be ideal as a combination treatment with chemotherapeutic drugs or other immunotherapies.</p>Significance:<p>These findings reveal new insights into how macrophage populations within the pancreatic cancer microenvironment can be modulated, providing the means to turn the microenvironment from immunosuppressive to immune-responsive.</p></div>
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