Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17

Abstract

Background: Lactate greatly contributes to the regulation of intracellular communication within the tumor microenvironment (TME). However, the role of lactate in pituitary adenoma (PA) invasion is unclear. In this study, we aimed to clarify the effects of lactate on the TME and the effects of TME on PA invasion. Methods: To explore the correlation between TME acidosis and tumor invasion, LDHA and LAMP2 expression levels were quantified in invasive (n = 32) and noninvasive (n = 32) PA samples. The correlation between immune cell infiltration and tumor invasion was evaluated in 64 PAs. Critical chemokine and key signaling pathway components were detected by qPCR, Western blotting, siRNA knockdown, and specific inhibitors. The functional consequences of CCR4 signaling inhibition were evaluated in vitro and in vivo . Results: Lactate was positively associated with PA invasion. Of the 64 PA tissues, invasive PAs were related to high infiltration of M2-like tumor-associated macrophages (TAMs) (P < 0.05). Moreover, lactate secreted from PA cells facilitated M2 polarization via the mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion via the CCL17/CCR4/mTORC1 axis. According to univariate analysis of clinical data, high CCL17 expression was associated with larger tumor size (P = 0.0438), greater invasion (P = 0.0334), and higher susceptibility to postoperative recurrence (P = 0.0195) in human PAs. Conclusion: This study illustrates the dynamics between PA cells and immune TME in promoting PA invasion via M2 polarization. CCL17 levels in the TME are related to the PA invasiveness and clinical prognosis, and the CCL17/CCR4/mTOCR1 axis may serve as potential therapeutic targets for Pas.

Development and Validation of Nomogram to Preoperatively Predict Intraoperative Cerebrospinal Fluid Leakage in Endoscopic Pituitary Surgery: A Retrospective Cohort Study

“…This result was supported by Karnezis et al Their research examined 1,108 people with pituitary adenomas and 53 people with craniopharyngiomas who underwent endoscopic sellar surgery, and mild liver disease was revealed to be a risk factor for iCSF leakage (OR=3.636, p =0.046), which usually lead to low albumin levels. Based on the review by Wang et al, lower albumin levels function as a biomarker for immune dysfunction (24), and Zhang et al discovered that invasive PAs showed higher infiltration of M2-like tumor-associated macrophages (25), which have an anti-inflammatory phenotype (26). We suggest that lower albumin levels may act as a biomarker for an anti-inflammatory immune environment in PAs, which is suggestive of invasive tumor behavior.…”

“…Based on the review by Wang et al, lower albumin levels function as a biomarker for immune dysfunction ( 24 ), and Zhang et al. discovered that invasive PAs showed higher infiltration of M2-like tumor-associated macrophages ( 25 ), which have an anti-inflammatory phenotype ( 26 ). We suggest that lower albumin levels may act as a biomarker for an anti-inflammatory immune environment in PAs, which is suggestive of invasive tumor behavior.…”

Research advances on the immune research and prospect of immunotherapy in pituitary adenomas

“…By stimulating tumor angiogenesis and inhibiting the anti-tumor immune response mediated by T cells, TAMs promote the proliferation, invasion, and metastasis of tumor cells [ 30 ]. Recent studies by Zhang et al have shown that PA may produce excess lactate, resulting in TME acidification, which reshapes TAMs into an M2-type phenotype and then secrets CCL17 through TAMs to enhance tumor invasion through the CCL17/CCR4/mTORC1 axis [ 31 ]. Meanwhile, M2 macrophages may play a role in neoangiogenesis in pituitary adenomas together with B cells, CD4 + T cells, and Foxp3 + lymphocytes [ 32 ].…”

“…In the PA stroma, CD68+ macrophages > CD4+ T cells and CD8+ T cells. [ 31 , 41 , 47 , 48 , 51 – 53 ] 35; 134; 28;35; 64; 115; 15 Immunohistochemistry; Computational approach; flow cytometry 2021; 2020; 2020; 2015; 2020; 2020; 2019 CD147 Invasion tumors > non-invasive tumors. [ 55 ] 55 Immunohistochemistry 2005 CD163 The most abundant type of immune cell in PitNETs, and mainly CD163 +.…”

Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

“…Furthermore, in murine and human melanoma, IL-1β has been shown to induce the expression of Ten-Eleven-Translocation-2, a DNA methylcytosine dioxygenase, sustaining the immunosuppressive functions of TAMs [ 65 ]. Additionally, cancer-cell-derived CCL2, CCL18, CCL17 and CXCL4 work in concert to polarize macrophages towards M2-like phenotypes [ 66 , 67 , 68 , 69 ].…”