Increased Circulating Chemokines and Macrophage Recruitment in Growing Vestibular Schwannomas

Abstract

BACKGROUND:There is evidence that macrophage infiltration in the tumor microenvironment promotes vestibular schwannoma (VS) growth. Efficacy of bevacizumab in NF2-associated VS demonstrates the value of therapies targeting the microvascular tumor microenvironment, and tumor-associated macrophages (TAMs) may represent another druggable target.OBJECTIVE:To characterize the relationship between growth, TAM infiltration, and circulating monocyte chemokines in a large cohort of patients with VS.METHODS:Immunostaining for Iba1 (macrophages), CD31 (endothelium), and fibrinogen (permeability) was performed on 101 growing and 19 static sporadic VS. The concentrations of monocyte-specific chemokines were measured in the plasma of 50 patients with growing VS and 25 patients with static VS.RESULTS:The Iba1+ cell count was significantly higher in growing as compared with static VS (592 vs 226/×20 HPF, P=<0.001). Similarly, the CD31+ % surface area was higher in growing VS (2.19% vs 1.32%, P = .01). There was a positive correlation between TAM infiltration and VS growth rate, which persisted after controlling for the effect of tumor volume (aR2 = 0.263, P=<0.001). The plasma concentrations of several monocytic chemokines were higher in patients with growing rather than static VS.CONCLUSION:There is a strong positive correlation between TAM infiltration and volumetric growth of VS, and this relationship is independent of tumor size. There is a colinear relationship between TAM infiltration and tumor vascularity, implying that inflammation and angiogenesis are interlinked in VS. Chemokines known to induce monocyte chemotaxis are found in higher concentrations in patients with growing VS, suggestive of a potential pathophysiological mechanism.

High-Dimensional Imaging of Vestibular Schwannoma Reveals Distinctive Immunological Networks Across Histomorphic Niches inNF2-related Schwannomatosis

“…The inflammatory mediators secreted from the TME likely drives recruitment of monocytes into the tumour and support the TAM-rich identity of VS. Indeed, previous immune profiling studies in VS have shown that schwannoma cells and TAMs secrete inflammatory factors, such as interleukin (IL)-2, IL-6 and CCL20, and that increased levels of circulating monocytic chemokines are observed in plasma samples from growing VS cases 45,46 . Supporting this, we have shown that classically-activated TAMs and transitioning monocytes have extensive interaction networks in Antoni A regions, namely with other myeloid cells, vasculature and some Schwann cell populations.…”

New Insights into Fibrotic Signaling in Cancer

“…Clinical studies highlight the crucial roles of macrophages in cancer therapy response and resistance, including chemotherapy, radiotherapy, and PDL1-based immunotherapy (Furuse et al, 2020;. Moreover, clinical trials of macrophage-targeted therapies have been started such as the engineered mononuclear phagocytes (Brempelis et al, 2020) and chimeric antigen receptor macrophages (CAR-M) (Klichinsky et al, 2020;, these therapeutic approaches stem from bench-top discoveries like recruitment and differentiation (Hannan et al, 2023), functional reprogramming (Willingham et al, 2012), and integration (Dang et al, 2021), highlighting the importance of basic research and preclinical study for the development of effective cancer treatment.…”

Tumour-associated macrophages: versatile players in the tumour microenvironment

“…Clinical studies highlight the crucial roles of macrophages in cancer therapy response and resistance, including chemotherapy, radiotherapy, and PDL1-based immunotherapy ( Furuse et al, 2020 ; Liu et al, 2020 ). Moreover, clinical trials of macrophage-targeted therapies have been started such as the engineered mononuclear phagocytes ( Brempelis et al, 2020 ) and chimeric antigen receptor macrophages (CAR-M) ( Klichinsky et al, 2020 ; Wang et al, 2022 ), these therapeutic approaches stem from bench-top discoveries like recruitment and differentiation ( Hannan et al, 2023 ), functional reprogramming ( Willingham et al, 2012 ), and integration ( Dang et al, 2021 ), highlighting the importance of basic research and preclinical study for the development of effective cancer treatment.…”