CD13^hi Neutrophil-like myeloid-derived suppressor cells exert immune suppression through Arginase 1 expression in pancreatic ductal adenocarcinoma

Abstract

Perineural invasion and immunosuppressive tumor microenvironment are the distinct features of pancreatic ductal adenocarcinoma (PDAC). Heterogeneous myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity, posing obstacles for cancer immunotherapy. Increasing evidences have demonstrated the accumulation of MDSCs in PDAC patients. However, the role of MDSCs in perineural invasion of PDAC and the existence of novel MDSC subsets during PDAC remain unclear. This study found that lymphocytic perineural cuffs were frequently present in chronic pancreatitis (CP) tissues and adjacent non-neoplastic pancreatic tissues (ANPTs), but not in PDAC with perineural invasion. Meanwhile, we found that neutrophil-like MDSCs (nMDSCs), but not monocyte-like MDSCs (mMDSCs), were significantly increased in PBMCs and tumor tissues of PDAC patients. Further observation identified two distinct subsets of nMDSCs, CD13 and CD13 nMDSCs in PDAC patients, which have not been reported previously. Despite a similar morphology, CD13 nMDSCs expressed higher levels of CD11b, CD33, CD16 and arginase 1 but lower levels of CD66b than CD13 nMDSCs. Importantly, CD13 MDSCs, compared with CD13 nMDSCs, more effectively suppressed alloreactive T cell responses via an arginase-1-related mechanism. After tumor resection, the circulating CD13 nMDSCs were decreased markedly. PDAC patients with more CD13 nMDSCs had a shorter overall survival than those with less CD13 nMDSCs. To conclude, we identified two novel MDSC subsets with different characteristics and functions in PDAC, demonstrated the association of the two MDSC subsets with cancer progression, and explored their roles in perineural invasion and immune escape of PDAC.

Neutrophil Diversity in Health and Disease

“…Both these markers separated cells with similar morphology but with different expression profiles of membrane proteins and functions, and perhaps with distinct prognostic significance. Indeed, PDAC patients with more CD13 high neutrophils had a shorter overall survival than those with fewer CD13 high neutrophils [116], and patients with an increased fraction of the ILT3 high subset had a shorter median survival than patients with a smaller ILT3 high fraction [117]. The above observations regarding candidate markers for the potential identification of neutrophil subpopulations in malignancies (and possibly other diseases), although attractive, remain to be further validated.…”

“…In chronic lymphocytic leukemia, leukemic lymphocytes promoted the ex vivo differentiation of neutrophils into a more immunosuppressive population, characterized as CD16 high CD62L dim , compared with neutrophils that were not exposed to these cells or their conditioned media [115]. Finally, two distinct neutrophil populations of CD13 high and CD13 low neutrophils, that are present both in blood and tumor tissues, were described in patients with pancreatic ductal adenocarcinoma (PDAC) [116], whereas two different circulating neutrophil populations were found based on the differential expression of immunoglobulin-like transcript 3 (ILT3)high and lowin NSCLC patients [117]. Both these markers separated cells with similar morphology but with different expression profiles of membrane proteins and functions, and perhaps with distinct prognostic significance.…”

Neutrophil heterogeneity: Bona fide subsets or polarization states?

“…PMN‐MDSCs also demonstrate heterogeneity, containing both immature and mature neutrophils. CD13 expression on PMN‐MDSCs has also been used to define a greater T cell suppressive activity and higher percentage of CD13 + PMN‐MDSCs is correlated with worse clinical outcomes in cancer patients . Although often referred to in the context of cancer, MDSCs have also been noted to play roles in sepsis, infection, and cardiovascular disease …”

Neoadjuvant Therapy Remodels the Pancreatic Cancer Microenvironment via Depletion of Protumorigenic Immune Cells

“…Over the past decade, neoadjuvant therapy (neoTx) has dramatically improved prognosis of patients with locally advanced and borderline resectable pancreatic cancer (1,2); thus, understanding its mechanisms of action is of high and immediate clinical relevance. Although traditionally considered to be immunosuppressive, growing evidence suggests that neoTx exerts its beneficial effects by restoration of the local antitumoral immune response (3)(4)(5).…”