Pancreatic adenocarcinoma induces bone marrow mobilization of myeloid-derived suppressor cells which promote primary tumor growth

Abstract

Purpose Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells that are upregulated in cancer. Little is known about the prevalence and importance of MDSC in pancreas adenocarcinoma (PA). Experimental Design Peripheral blood, bone marrow, and tumor samples were collected from pancreatic cancer patients, analyzed for MDSC (CD15+CD11b+) by flow cytometry, and compared to cancer free controls. The suppressive capacity of MDSC (CD11b+Gr-1+) and the effectiveness of MDSC depletion were assessed in C57BL/6 mice inoculated with Pan02, a murine PA, and treated with placebo or zoledronic acid, a potent aminobisphosphonate previously shown to target MDSC. The tumor microenvironment was analyzed for MDSC (Gr1+CD11b+), effector T cells, and tumor cytokine levels. Results Patients with PA demonstrated increased frequency of MDSC in the bone marrow and peripheral circulation which correlated with disease stage. Normal pancreas tissue showed no MDSC infiltrate, while human tumors avidly recruited MDSC. Murine tumors similarly recruited MDSC that suppressed CD8+ T cells in vitro and accelerated tumor growth in vivo. Treatment with zoledronic acid impaired intratumoral MDSC accumulation resulting in delayed tumor growth rate, prolonged median survival, and increased recruitment of T cells to the tumor. This was associated with a more robust type 1 response with increased levels of IFN-γ and decreased levels of IL-10. Conclusions MDSC are important mediators of tumor-induced immunosuppression in pancreatic cancer. Inhibiting MDSC accumulation with zoledronic acid improves the host anti-tumor response in animal studies suggesting that efforts to block MDSC may represent a novel treatment strategy for pancreatic cancer.

RG7212 Anti-TWEAK mAb Inhibits Tumor Growth through Inhibition of Tumor Cell Proliferation and Survival Signaling and by Enhancing the Host Antitumor Immune Response

“…S1D). Activity in the aggressive Pan02 model was modest but comparable to the best response observed with standard-of-care cytotoxic agent gemcitabine (37) or immunomodulating agents (38). Tumor growth and tumor-induced immunosuppression is multifactorial and single-agent therapies are unlikely to be curative, but RG7212 monotherapy activity and lack of toxicity suggest that combination therapies should be explored.…”

Genetics and biology of pancreatic ductal adenocarcinoma

“…In PDAC, MDSC infiltrations are observed as early as the preinvasive PanIN lesions and progressively increase throughout the evolution of the tumor (Clark et al 2007;Zhao et al 2009;Zhang et al 2014b). G-CSF and GM-CSF (Bayne et al 2012;Pylayeva-Gupta et al 2012); IL-3, M-CSF, and IL-6 (Serafini et al 2006); and CCL2 chemokine (Tjomsland et al 2011) have been shown to be released by PDAC cancer cells to promote MDSC recruitment to the tumor microenvironment (Porembka et al 2012) and suppress antigen-specific T cells. G-CSF and GM-CSF expression is driven by oncogenic KRAS via the RAS/MEK/MAPK pathway through the ETS transcription factor (Bayne et al 2012); correspondingly, MEK or PI3K inhibitors can attenuate the release of G-CSF and improve survival in an orthotopic allograft mouse model established by injecting primary ductal epithelial cells (PDECs) isolated from a GEMM of PDAC into the pancreata of syngeneic C57Bl/6 mice (Cox and Olive 2012;Pylayeva-Gupta et al 2012).…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…Another type of tumorassociated immune cell that has gained a lot of recent attention is the myeloid-derived suppressor cell (MDSC) [51,52]. MDSCs represent a heterogeneous group of immature [198][199][200].…”