The immunosuppressive phenotype of tumor-infiltrating neutrophils is associated with obesity in kidney cancer patients

Abstract

Infiltrating tumor neutrophils and myeloid-derived suppressor cells represent major populations in the tumor microenvironment that contribute to tumor progression. However, the phenotype of circulating and tumor-associated neutrophils, and the impact of cancer patients' metabolic state on neutrophil function need further characterization. Here we show that in kidney cancer patients, circulating neutrophils display an altered immature-like phenotype, and an activated/primed metabolic state. Circulating immature-like neutrophils acquire an activated phenotype upon migration into the tumor tissue, characterized by high expression of the immunosuppressive enzyme arginase-1, and active granule release. Interestingly, obesity and adipose tissue distribution were significantly associated with this activated phenotype of neutrophils, including the release of arginase-1 in the tumor tissue. These results provide a possible functional relationship between the metabolic status of the patients and disease progression, through an active immunosuppressive role of neutrophils within the kidney tumor microenvironment.

Chemotherapy-Induced Neutropenia as a Prognostic Factor in Patients With Advanced Epithelial Ovarian Carcinoma

“…Moreover, previous studies have recognized that inflammation in tumor microenvironment plays crucial roles in tumor cell survival, proliferation, and migration. [26][27][28][29] Neutrophils enhance tumor angiogenesis by releasing proinflammatory cytokines and matrix metal-loproteinase9 (MMP9). In addition, neutrophils restrain antitumor immune by releasing argininase 1 to inhibit T cell function.…”

The Interface of Cancer, Their Microenvironment and Nanotechnology

“…The pro-metastatic and proangiogenic role of TANs is mainly due to its capacity to secrete several proangiogenic or immunosuppressive molecules, such as VEGF, IL-1β, TGFα, FGF2; enzymes involved in ECM remodeling such as MMP9 and several chemokines (i.e., CXCL1, CCL3, CCL4, CXCL8, CXCL9 and CXCL10) [66]. In obese patients diagnosed with kidney cancer, the increased expression of arginase-1 was involved in T cell suppression [67]. Several evidence showed the presence of inflammatory CD66b+ neutrophils in both TME and peripheral blood in cancer patients and correlate their presence with poor clinical outcome [68,69].…”

OMIP‐100: A flow cytometry panel to investigate human neutrophil subsets

“…autoimmune disease [16,17], and cancer [18][19][20], with sepsis being perhaps the most extreme pathological case for changes and creation of circulating neutrophil subsets that can be linked to sepsis outcomes [14]. However, changes in conventional neutrophil maturity/ ontogeny markers [21,22] are also seen during priming, transmigration, and activation, which have been linked to functional responses or disease states [23,24].…”

“…Traditionally considered to be just short‐lived cells that are pre‐programmed to carry out the above functions before undergoing apoptotic clearance, neutrophils have recently been recognized for their capacity to extend their lifespan [3] and display profound transcriptional plasticity, leading to the acquisition of novel functions such as the modulation of adaptive immunity [4–7]. Key studies have identified novel activation marker expression or preferential activity of neutrophil subsets in response to infection [8–12], sepsis [13–15], autoimmune disease [16, 17], and cancer [18–20], with sepsis being perhaps the most extreme pathological case for changes and creation of circulating neutrophil subsets that can be linked to sepsis outcomes [14]. However, changes in conventional neutrophil maturity/ontogeny markers [21, 22] are also seen during priming, transmigration, and activation, which have been linked to functional responses or disease states [23, 24].…”