Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment

Abstract

Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the crosstalk between pancreatic cancer (PC) and its TAS in primary human cell culture models. Upon exposure of TAS to PC cell-conditioned media, we documented robust secretion of IL-6 and IL-8. This TAS response was MyD88-dependent and sufficient to directly suppress both CD4+ and CD8+ T cell proliferation, inducing Th17 polarization at the expense of Th1. We found that patients possessed a similar shift in circulating effector memory Th17:Th1 ratios compared to healthy controls. The TAS response also directly suppressed CD8+ T cell-mediated cytotoxicity. Overall, our results demonstrate how TAS contributes to the production of an immunosuppressive tumor microenvironment in pancreatic cancer.

IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy

“…Our findings that IL-6 and IL-8 are synergistically increased in the conditioned media of PC/TAS cell co-cultures agrees with previously published work from our group [44]. However, here we arrived at this finding through the unbiased screening of 41 cytokines/chemokines, whereas in our previous work, IL-6 and IL-8 were preselected for their study in the tumor microenvironment [44]. In the context of cachexia, IL-6 is a well-studied cytokine.…”

“…It was first described as a neutrophil chemoattractant secreted by monocytes and macrophages [48]. However, many other cell types are now known to secrete IL-8, including neutrophils [49], lymphocytes [50], fibroblasts [51], endothelial cells [52], as well as several types of cancer cells [38,44,[53][54][55]. In this latter regard, tumor-derived IL-8 can function in an autocrine manner to facilitate oncogenic signaling and pro-metastatic processes, and in a paracrine manner to alter the immune cell populations in the tumor microenvironment and induce angiogenesis [56].…”

Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking

“…Supernatant from cultured fibroblasts was collected at 48 hours after treatment with AMO and was then diluted 500-fold with PBS (39). Secreted procollagen 1a in diluted samples was measured with an ELISA kit according to the manufacturer's instructions (R&D Systems).…”

Regional immunotherapy for liver and peritoneal metastases

“…Pancreatic cancer cells secrete granulocyte‐macrophage colony stimulating factor (GM‐CSF) which, under some circumstances, inhibits T cell anti‐tumor activity through support of suppressive myeloid cells . Pancreatic cancer can induce release of IL‐6 and IL‐8 from the stroma which may decrease T cell proliferation . Considering the importance of the immune landscape in shaping pancreas cancer biology, immunotherapy is a rational approach for advanced pancreatic adenocarcinoma.…”

“…25 Pancreatic cancer can induce release of IL-6 and IL-8 from the stroma which may decrease T cell proliferation. 26 Considering the importance of the immune landscape in shaping pancreas cancer biology, immunotherapy is a rational approach for advanced pancreatic adenocarcinoma.…”