Distinct chemotherapy‐associated anti‐cancer immunity by myeloid cells inhibition in murine pancreatic cancer models

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with an extremely poor prognosis. Chemotherapy, such as gemcitabine (GEM), is the only treatment for PDAC patients who are not suitable for radical surgical treatment; however, its anti‐tumor efficacy is limited. In this study, we investigated the host immune system response in murine PDAC models undergoing GEM treatment. We found that PDAC tumor tissues were infiltrated with a substantial number of Gr‐1+ myeloid cells and had relatively small numbers of CD4+ and CD8+ cells. In addition, there were increased numbers of myeloid cells expressing CD11b+ and Gr‐1+ in peripheral blood. When mice with PDAC tumors in the intraperitoneal cavity or liver were treated with GEM, numbers of myeloid cells in tumor tissues and in peripheral blood decreased. In contrast, numbers of CD4+ or CD8+ cells increased. In peripheral blood, the numbers of CD8+ cells expressing interferon‐gamma (IFN‐γ) were higher in GEM‐treated mice than in untreated mice. In addition, GEM treatment in combination with myeloid cell depletion further prolonged the survival of PDAC mice. The gene expression profile of peripheral blood in myeloid cell‐depleted PDAC mice treated with GEM showed biological processes related to anti‐cancer immunity, such as natural killer cell‐mediated cytotoxicity, type I IFN signaling, and co‐stimulatory signaling for T cell activation. Thus, in PDAC murine models, GEM treatment was associated with an immune response consistent with an anti‐cancer effect, and depletion of myeloid‐lineage cells played an important role in enhancing anti‐cancer immunity associated with GEM treatment.

Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis

“…Previously, we observed changes of the host immune response by GEM treatment; specifically, there was a decreased number of MDSCs in tumor tissues and peripheral blood, an increase in the frequency of CD4+ and CD8+ T cells, and enhanced functional activity of CD8+ T cells for killing tumor cells. 8 We also observed that the tumors of PDAC mice treated with GEM showed an increase in PD-1 expression, which was abolished by anti-PD-1 Ab treatment (online supplemental figure S2). Thus, GEM plus anti-PD-1 Ab treatment enhanced the anticancer immune effect compared with single GEM treatment.…”

“…19 We previously reported that MDSCs potentially diminished the effect of GEM treatment, and the ablation of myeloid-derived cells augmented the anti-cancer effect of GEM, which was mediated by CD8+ T cells. 8 From the current results, anti-PD-1 Ab treatment appears to be a promising choice as a combinatorial agent for PDAC chemotherapy. Macrophages are reportedly affected by anti-PD-1 Ab treatment 20 or can be directed toward M1 macrophages in the PD-1 knock-out condition.…”

The Role of Tumor-Associated Myeloid Cells in Modulating Cancer Therapy

“…Depletion of myeloid-lineage cells enhanced anti-cancer immunity associated with gemcitabine (GEM) treatment in mice with pancreatic ductal adenocarcinoma (PDAC) tumors (65). GEM is a nucleoside analog used as first-line treatment.…”

“…Following GEM treatment, myeloid cells in tumor tissues and in peripheral blood decreased while numbers of CD4 + or CD8 + cells increased suggesting that anti-cancer immunity was enhanced. In addition, concurrent treatment of mice with GEM and further depletion of myeloid cells using an anti-GR-1 antibody significantly prolonged survival (65). Inflammatory breast cancer (IBC) is often characterized by overexpression of epidermal growth factor receptors 1 and/or 2 (ErbB1, ErbB2) that activate downstream survival pathways phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and MAPK (66).…”

Rapid diagnosis of infection etiology in febrile pediatric oncology patients using infrared spectroscopy of leukocytes

“…These antibodies bind to the pathogens and thus marking them to be attacked by the innate cells. In addition, it is worthwhile to mention that some of the oncology patients are undergoing chemotherapy treatment which affects their immune system cells causing a severe reduction in the leukocytes count [26]. In case of intracellular pathogens, the role of CD + 8 T-cells, which are stimulated by CD + 4 T-cells, is to kill the host cells that harbor foreign molecules (such as for a virus).…”