IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors

Abstract

BackgroundHigh serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective.MethodsIL-6 and IL-6R blockade was applied in an IL-6-mediated immunotherapy-resistant TC-1 tumor model (TC-1.IL-6) and immunotherapy-sensitive TC-1.control. Effects on therapeutic vaccination-induced tumor regression, recurrence and survival as well on T cells and myeloid cells in the tumor microenvironment were studied. The effects of IL-6 signaling in macrophages under therapy conditions were studied in Il6rafl/fl×LysMcre+ mice.ResultsOur therapeutic vaccination protocol elicits a strong tumor-specific CD8+ T-cell response, leading to enhanced intratumoral T-cell infiltration and recruitment of tumoricidal macrophages. Blockade of IL-6 signaling exacerbated tumor outgrowth, reflected by fewer complete regressions and more recurrences after therapeutic vaccination, especially in TC-1.IL-6 tumor-bearing mice. Early IL-6 signaling blockade partly inhibited the development of the vaccine-induced CD8+ T-cell response. However, the main mechanism was the malfunction of macrophages during therapy-induced tumor regression. Therapy efficacy was impaired in Il6rafl/fl×LysMcre+ but not cre-negative control mice, while no differences in the vaccine-induced CD8+ T-cell response were found between these mice. IL-6 signaling blockade resulted in decreased expression of suppressor of cytokine signaling 3, essential for effective M1-type function in macrophages, and increased expression of the phagocytic checkpoint molecule signal-regulatory protein alpha by macrophages.ConclusionIL-6 signaling is critical for macrophage function under circumstances of immunotherapy-induced tumor tissue destruction, in line with the acute inflammatory functions of IL-6 signaling described in infections.

Biomimetic “Gemini nanoimmunoregulators” orchestrated for boosted photoimmunotherapy by spatiotemporally modulating PD-L1 and tumor-associated macrophages

“…Also, the inflammatory cytokines ( e . g ., IL-6) secreted by M1 type macrophages could enhance CTLs recruitment 43 . Excitingly, after “Gemini nanoimmunoregulators” treatment, the rate of CD8 + T cells increased to 36.5 ± 8.4% (4.9-fold of the control group), which was due to the synergistic effect of PM@RM-T7 and PR@RM-M2.…”

Differentially polarized macrophages show diverse proangiogenic characteristics under normo- and hyperglycemic conditions

“…Among the anti-angiogenic genes, STAT1 and its downstream target CXCL9 were upregulated in macrophages induced by IL-6, both in normal and high glucose conditions. IL-6 activates JAK-STAT signaling upon binding to its receptor, predominantly activating STAT1 and STAT3 [34][35][36] . Additionally, we found that IL-6 stimulation increased the expression of cyclin-dependent kinase inhibitor (CDKN1A, also known as p21 Clip1/Waf1 ), which regulates cell cycle progression.…”

Exploration of the effect of Celastrol on protein targets in nasopharyngeal carcinoma: Network pharmacology, molecular docking and experimental evaluations

“…Cytokines of the IL6 family play an important role in mediating the tumor microenvironment to promote tumor inflammation and often act as diagnostic or prognostic biomarkers of tumors ( Abaurrea et al, 2021 ). Although high IL6 expression is thought to have a tumor-promoting effect in many tumors, IL6 blockade therapy may exacerbate tumor growth because high IL6 expression increases the expression of cytokine signaling 3, which is required for the maintenance of antitumor M1 macrophage function ( Beyranvand Nejad et al, 2021 ). In a study on melanoma, IL6-overexpressing tumors were found to grow significantly slower in mice with concomitant CD8 + T cell activation.…”