Myeloid‐derived suppressor cells: Bridging the gap between inflammation and pancreatic adenocarcinoma

Abstract

Pancreatic cancer has been identified as one of the deadliest malignancies because it remains asymptomatic and usually presents in the advanced stage. Tumour immune evasion is a well‐known mechanism of tumorigenesis in various forms of human malignancies. Chronic inflammation via complex networking of various inflammatory cytokines in the local tissue microenvironment dysregulates the immune system and support tumour development. Pro‐inflammatory mediators present in the tumour microenvironment increase the tumour burden by causing immune suppression through the generation of myeloid‐derived suppressor cells (MDSCs) and T regulatory cells. These cells, along‐with myofibroblasts, create a highly immunosuppressive and resistant tumour microenvironment and are thus considered as one of the culprits for the failure of anti‐cancer chemotherapies in pancreatic adenocarcinoma patients. Targeting these MDSCs using various combinatorial approaches might have the potential for abrogating the resistance and suppressive nature of the pancreatic tumour microenvironment. Therefore, there is more curiosity in studying the crosstalk of MDSCs with other immune cells during pathological conditions and the underlying mechanisms of immunosuppression in the current scenario. In this article, the possible role of MDSCs in inflammation‐mediated tumour progression of pancreatic adenocarcinoma has been discussed.

The heterogeneity of CAFs and immune cell populations in the tumor microenvironment of pancreatic adenocarcinoma

“…One of the abundant immune cells that play a crucial role in the progression of PDAC is myeloid cells [29] . Of those, myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are some of the most studied types [29] . Although with similar phenotypes and surface markers, MDSCs and TAMs are two distinct populations [Figure 2] [29] .…”

“…Of those, myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are some of the most studied types [29] . Although with similar phenotypes and surface markers, MDSCs and TAMs are two distinct populations [Figure 2] [29] . Sophisticated cross-talk between these cells and tumor cells collectively leads to resistance to chemotherapy, inhibition of effector T cell, and promotion of tumor invasiveness and metastases.…”

“…MDSCs are characterized by an immature, immune suppressive phenotype [30] . MDSCs are classified into two subsets: 1-polymorphonuclear-MDSC (PMN-MDSC) that share markers expressed on neutrophils, and 2-monocytic-MDSC (M-MDSC) that share markers expressed on monocytes and macrophages [6,29] . A third subpopulation of MDSCs exists, representing a common progenitor of MDSCs, referred to as earlystage MDSC or eMDSC [29,31,32] .…”

“…A third subpopulation of MDSCs exists, representing a common progenitor of MDSCs, referred to as earlystage MDSC or eMDSC [29,31,32] . This subpopulation has yet to be functionally evaluated in PDAC [29] . MDSCs in PDAC are bone marrow-derived, and their formation is driven by kras, tumor-derived granulocytemacrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF) [30] .…”

IL‐6 is associated with expansion of myeloid‐derived suppressor cells and enhanced immunosuppression in pancreatic adenocarcinoma patients

“…Incessant secretion of pro-inflammatory cytokines during chronic inflammation might stimulate the accumulation and expansion of MDSCs, thereby inhibit normal T-cell-mediated anti-tumour immunity and lead to malignant transformation. [20][21][22] MDSCs were found to display their immunosuppressive activity through ARG-1, 23,24 inducible nitric oxide synthase (iNOS), 20 PD-L1, 25 cyclooxygenase 2 (COX2) 26 and by ROS production. 27 Inflammatory tumour stroma can alter the normal immune cell phenotype and encourage the differentiation of immature myeloid cells (IMCs) into MDSCs, thereby leading to immunosuppression.…”