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

Abstract

BackgroundPancreatic ductular adenocarcinoma (PDAC) is among the most dreadful of malignancies, in part due to the lack of efficacious chemotherapy. Immune checkpoint inhibitors, including anti-programmed cell death 1 (anti-PD-1) antibodies, are novel promising forms of systemic immunotherapy. In the current study, we assessed whether gemcitabine (GEM) combined with anti-PD-1 antibody treatment was efficacious as immunochemotherapy for advanced PDAC using a murine model of liver metastasis.MethodsThe murine model of PDAC liver metastasis was established by intrasplenically injecting the murine pancreatic cancer cell line PAN02 into immunocompetent C57BL/6J mice. The mice were treated with an anti-PD-1 antibody, GEM, or a combination of GEM plus anti-PD-1 antibody, and compared with no treatment (control); liver metastases, immune cell infiltration, gene expression, immune cell response phenotypes, and overall survival were investigated.ResultsIn the metastatic tumor tissues of mice treated with GEM plus anti-PD-1 antibody, we observed the increased infiltration of Th1 lymphocytes and M1 macrophages. Gene expression profile analysis of peripheral blood cells obtained from mice treated with GEM plus anti-PD-1 antibody clearly highlighted T cell and innate immune signaling pathways. Survival of PDAC liver metastasis mice was significantly prolonged by the combination therapy (median survival, 66 days) when compared with that of GEM alone treatment (median survival, 56 days). Expanded lymphocytes, which were isolated from the splenocytes of PDAC liver metastasis mice treated with GEM plus anti-PD-1 antibody, had an increased number of M1 macrophages.ConclusionThe combination of anti-PD-1 antibody immunotherapy with GEM was beneficial to treat a murine model of PDAC liver metastasis by enhancing the immune response mediated by Th1 lymphocytes and M1 macrophages and was associated with CD8+ T cells.

Immunotherapy Combined with Metronomic Dosing: An Effective Approach for the Treatment of NSCLC

“…Moreover, mice administered with this combinatorial therapy demonstrated enhanced intratumoral infiltration of cells of both the innate and adaptive immune system, such as CD11b+F4/80+Ly6C+Ly6G− inflammatory monocytes, CD11b+F4/80highCD206+ M1 macrophages and IFN-γ-expressing CD8a+ and CD4+ T cells with well-known proinflammatory/antitumor properties. In addition, the authors observed a significant upregulation in gene expression of several effector cytokines and chemokines related to anticancer immunity in tumor-infiltrating inflammatory cells [ 38 ]. Another interesting study revealed that in mice inoculated subcutaneously (sc) with LLC cells, administration of both gemcitabine and anti-PD1 resulted in reduced tumor volume and prolonged overall survival of recipients compared to those that received only gemcitabine or anti-PD1.…”

The Heterogeneity of the Tumor Microenvironment as Essential Determinant of Development, Progression and Therapy Response of Pancreatic Cancer

“…However, multiple clinical trials evaluating CD40 agonists for the treatment of PDAC in combination with chemotherapeutic or targeted agents are ongoing (NCT03214250; NCT04536077; NCT04807972; NCT04888312) and may yield more promising results. Furthermore, the combination of an anti-PD-1 antibody with Gemcitabine showed a beneficial effect in a murine PDAC liver metastasis model, which was explained by an increase of M1-macrophages and a TH1 response [ 182 ].…”

“…However, multiple clinical trials evaluating CD40 agonists for the treatment of PDAC in combination with chemotherapeutic or targeted agents are ongoing (NCT03214250; NCT04536077; NCT04807972; NCT04888312) and may yield more promising results. Furthermore, the combination of an anti-PD-1 antibody with Gemcitabine showed a beneficial effect in a murine PDAC liver metastasis model, which was explained by an increase of M1-macrophages and a TH1 response [182]. Since specific targeting of macrophages spares other immunosuppressive monocytic cell populations which may impair the therapeutic efficacy, targeting of the integrin CD11b/CD18 which highly expressed on several myeloid cell subsets has been suggested as a promising strategy for PDAC treatment.…”

Understanding the immune response and the current landscape of immunotherapy in pancreatic cancer

“…This type of cell death is characterized by a necrolytic release of danger signals that can modify the stroma, change cytokine rates, reduce the presence of suppressive cells such as MDSCs and Tregs, promote the expression of molecules of the major histocompatibility complex (MHC) in cancerous cells and stimulate DC maturation[ 87 ]. In animal models, a synergetic effect has been observed between the combination of gemcitabine and anti-PDL1[ 88 ].…”