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Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

ABSTRACT: Immunotherapy is revolutionizing cancer treatment but can trigger toxicities that remain poorly understood. Here, by comprehensively analyzing mouse models following anti-CD40 therapy, we found an interdependent induction of the cytokines IFN-g and IL-12, which caused inflammatory pathology in various tumor-free tissues. In the liver, Kupffer cells mediated toxicity by sensing lymphocyte-derived IFN-g and producing IL-12, highlighting the vulnerability of tissue-resident macrophages to promote toxicity when reacting to proinflammatory cues. Conversely, dendritic cells drove tumor control but were dispensable for toxicity. We further show that liver macrophages, IL-12, and IFN-g were not toxic themselves, but prompted a neutrophil response that determined the severity of tissue damage. Similar inflammatory pathways characterized immunotherapy-related adverse events in cancer patients. These findings implicate resident macrophages and neutrophils as mediators and effectors of aberrant inflammation, and suggest distinct cellular mechanisms of toxicity and antitumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE175737 | GEO | 2021/06/03

REPOSITORIES: GEO

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Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

Project description:Immunotherapy is revolutionizing cancer treatment, but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions remains poorly understood. Here, using anti-CD40-treatment in mice as a model of Th1-promoting immunotherapy, we show liver macrophages’ vulnerability to promote local adverse events. Mechanistically, tissue-resident Kupffer cells mediate liver toxicity by sensing lymphocyte-derived IFN-g and producing IL-12. Conversely, dendritic cells are dispensable for toxicity but drive tumor control. Though macrophages, IL-12, and IFN-g are not necessarily toxic themselves, we find that they prompt a neutrophil response that determines the severity of tissue damage. We further show that similar inflammatory pathways characterize adverse events across tissues, following anti-PD-1 and anti-CTLA4 immunotherapies, and in humans. These findings implicate macrophages and neutrophils as mediators and effectors of aberrant inflammation in Th1-promoting immunotherapy, and suggest distinct mechanisms of toxicity and antitumor immunity.

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Phosphoproteomic analysis of IL-2 MSA and IL-12 MSA combination on T cell signaling

Project description:Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) due to low IL-12R expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing IL12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.

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Differential production of Type I IFN determines the reciprocal levels of IL-10 and proinflammatory cytokines produced by C57BL/6 and BALB/c macrophages

Project description:Pattern recognition receptors (PRR) detect microbial products and induce cytokines which shape the immunological response. Interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-Î±) and IL-1Î² are proinflammatory cytokines which can be essential for resistance against infection, but if produced at high levels, may contribute to immunopathology. In contrast, IL-10 is an immunosuppressive cytokine which dampens proinflammatory responses, but can also lead to defective pathogen clearance. The regulation of these cytokines is therefore central to the generation of an effective but balanced immune response. Here, we show that macrophages derived from C57BL/6 mice produce low levels of IL-12, TNF-Î± and IL-1Î², but high levels of IL-10 in response to TLR4 and TLR2 ligands LPS and PamCSK4, and Burkholderia pseudomallei a Gram-negative bacterium which activates TLR 2/4. In contrast, macrophages derived from BALB/c mice show a reciprocal pattern of cytokine production. Differential production of IL-10 in B. pseudomallei and LPS stimulated C57BL/6 and BALB/c macrophages was due to a type I IFN dependent, but IL-27 independent mechanism. Further, type I IFN contributed to differential IL-1Î² and IL-12 production in B. pseudomallei and LPS stimulated C57BL/6 and BALB/c macrophages, via both IL-10-dependent and independent mechanisms. These findings highlight key pathways responsible for the regulation of pro- and anti-inflammatory cytokines in macrophages and reveal how they may differ according to the genetic background of the host. Total RNA obtained from bone-marrow derived macrophages of C57BL/6 WT, C57BL/6 Ifnar1-/- and BALB/c mice stimulated with heat-killed Burkholderia pseudomallei or media as controls.

2016-09-07 | E-GEOD-79809 | biostudies-arrayexpress

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2016-09-07 | GSE79809 | GEO

Macrophage-restricted Interleukin-10 receptor-, but not IL-10 deficiency causes severe spontaneous colitis

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2006-01-01 | GSE3552 | GEO

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2008-06-13 | E-GEOD-4811 | biostudies-arrayexpress