Role of immune cells in pancreatic cancer from bench to clinical application

Abstract

Background:Pancreatic cancer (PC) remains difficult to treat, despite the recent advances in various anticancer therapies. Immuno-inflammatory response is considered to be a major risk factor for the development of PC in addition to a combination of genetic background and environmental factors. Although patients with PC exhibit evidence of systemic immune dysfunction, the PC microenvironment is replete with immune cells.Methods:We searched PubMed for all relevant English language articles published up to March 2016. They included clinical trials, experimental studies, observational studies, and reviews. Trials enrolled at Clinical trial.gov were also searched.Results:PC induces an immunosuppressive microenvironment, and intratumoral activation of immunity in PC is attenuated by inhibitory signals that limit immune effector function. Multiple types of immune responses can promote an immunosuppressive microenvironment; key regulators of the host tumor immune response are dendritic cells, natural killer cells, macrophages, myeloid derived suppressor cells, and T cells. The function of these immune cells in PC is also influenced by chemotherapeutic agents and the components in tumor microenvironment such as pancreatic stellate cells. Immunotherapy of PC employs monoclonal antibodies/effector cells generated in vitro or vaccination to stimulate antitumor response. Immune therapy in PC has failed to improve overall survival; however, combination therapies comprising immune checkpoint inhibitors and vaccines have been attempted to increase the response.Conclusion:A number of studies have begun to elucidate the roles of immune cell subtypes and their capacity to function or dysfunction in the tumor microenvironment of PC. It will not be long before immune therapy for PC becomes a clinical reality.

The clinical importance of tumour-infiltrating macrophages and dendritic cells in periampullary adenocarcinoma differs by morphological subtype

“…Tumour-educated TAMs facilitate progression of pancreatic cancer and promote angiogenesis, remodelling of stroma, epithelial-mesenchymal transition and extravasation of tumour cells [28, 29]. Previous studies have demonstrated that TAMs are associated with poor prognosis in pancreatic cancer [7, 8], which is in line with the findings of the present study encompassing the full spectrum of periampullary adenocarcinoma.…”

Oncolytic viral therapy for pancreatic cancer

“…In fact, PDA cells compose only a minority of tumor bulk, with the majority (up to 80%) being accounted for by fibrotic tissue and inflammatory cells. Early in the course of carcinogenesis, acute and chronic inflammation activate pancreatic stellate cells (PaSC), which in turn, trigger the accumulation of a dense extracellular matrix, thereby disrupting the architecture of normal pancreatic tissue and inducing a hypovascular and hypoxic microenvironment . Several systemic agents targeting the PDA desmoplastic stroma have been devised and tested, alone or with cytotoxic chemotherapy.…”

“…In addition to posing a physical barrier to the infiltration of cytotoxic immune cells, the PDA microenvironment is characterized by cytokines, chemokines, and suppressor cells that inhibit the activation and function of immune effectors . While infiltrating effector T cells are abundant in tumors that tend to respond to checkpoint inhibitors, such as melanoma or microsatellite unstable colorectal cancer, PDA tumors are infiltrated by fibroblasts, myeloid‐derived suppressor cells, and T regulatory cells but relatively few cytotoxic T cells .…”

Cancer Manipulation of Host Physiology: Lessons from Pancreatic Cancer

“…Macrophages arrive to sites of inflammation after neutrophils and persist longer [40]; indeed, they are one of the main cell types involved in chronic inflammation [11, 41]. They infiltrate tumors in response to DAMPs and other danger signals are released secondary to tissue stress and hypoxia (which might be a consequence of chemo-/radio-therapy).…”

“…They infiltrate tumors in response to DAMPs and other danger signals are released secondary to tissue stress and hypoxia (which might be a consequence of chemo-/radio-therapy). They also mount responses to attempt to counteract danger signals and tissue stress; these include angiogenesis , remodeling of the ECM, and clearance of cellular debris [41]. Importantly, in mouse models of pancreatitis, they have been found to directly promote ADM via release of the pro-inflammatory cytokines RANTES and TNF, which activate NF-κB in acinar cells and upregulate several ADM-related proteins such as MMP9 [42].…”