Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

Abstract

Immunological strategies to treat pancreatic cancer offer new therapeutic approaches to improve patient outcomes. Understanding alterations in the immune systems of pancreatic cancer patients will likely lead to advances in immunotherapy for the disease. We profiled peripheral blood leukocytes from pancreatic cancer patients (n D 22) and age-matched controls (n D 20) using flow cytometry. Immune profiling of pancreatic cancer patients identified phenotypic changes in various immune cell populations, including a population of immunosuppressive monocytes (CD14 C HLA-DR lo/neg ), which were shown to be increased in these patients. There was a correlation between the levels of CD14 C monocytes and the levels of CD14 C HLA-DR lo/neg monocytes in peripheral blood from pancreatic cancer patients. HLA-DR downregulation of monocytes was shown to occur through pancreatic cancer-derived exosome interactions with monocytes. In an in vitro model, exosomes from patient-derived xenograft cell lines and patient plasma decreased HLA-DR expression on CD14 C monocytes. Additionally, tumor-derived exosomes caused immune suppression in monocytes through altered STAT3 signaling, induction of arginase expression, and reactive oxygen species. These findings provide novel insights into the mechanisms that govern immunosuppression in pancreatic cancer. Understanding monocyte-exosome interactions could lead to novel immunotherapies for this disease.

Tumor-promoting effects of pancreatic cancer cell exosomes on THP-1-derived macrophages

“…Although a recent report demonstrated that PGE 2 -enhanced the expression of PD-L1 on murine F4/80 + macrophages and Ly-6C + myeloid-derived suppressor cells [ 55 ], we did not observe a change in PD-L1 expression on THP-1 macrophages treated with PDAC exosomes. However, others have recently reported that PANC-1 exosomes can reprogram murine J771.A1 macrophages or human monocytes to an M2-like (CD14 + HLA-DR lo , increased Arg1) phenotype [ 56 , 57 ]. Thus, the bioactive lipids from tumor cell exosomes could trigger pro-inflammatory pathways in several TME cell types.…”

Prostate cancer exosomes as modulators of the tumor microenvironment

“…More recent reports also point to this phenomenon, where monocytes stimulated with cancer cell-derived EV become alternatively-activated/M2-type macrophages, expressing elevated levels of VEGF, IL6, Cox2, and arginase-1 amongst many other tumor-supportive factors [92,93] . Similar modulation of myeloid cells are seen using pancreatic cancer exosomes, giving a suppressive CD14 + HLA-DR low/neg phenotype akin to those elevated within the circulation of patients [94] . Similarly, myeloma-derived EV present within the bone marrow microenvironment can activate myeloid-derived suppressor cells (MDSC) and promote progression [95] .…”

Comprehensive assessment of circulating immune cell populations in response to stereotactic body radiation therapy in patients with liver cancer

“…We previously used this systems-based approach to understand the interplay of tumor and immune system interactions. 14 , 15 Additionally, immune biomarkers have been identified in patients with non-small cell lung cancer that predict both survival and treatment-related toxicity after SBRT treatment. 16 In this study, high pretreatment neutrophil-to-lymphocyte ratios and lymphocytopenia were associated with poor outcomes.…”