Blocking IL-17A enhances tumor response to anti-PD-1 immunotherapy in microsatellite stable colorectal cancer

Journal for immunotherapy of cancer

2021 Jan 01

Liu, C;Liu, R;Wang, B;Lian, J;Yao, Y;Sun, H;Zhang, C;Fang, L;Guan, X;Shi, J;Han, S;Zhan, F;Luo, S;Yao, Y;Zheng, T;Zhang, Y;
PMID: 33462141 | DOI: 10.1136/jitc-2020-001895

Immune checkpoint inhibitors (ICIs), including anti-PD-1 therapy, have limited efficacy in patients with microsatellite stable (MSS) colorectal cancer (CRC). Interleukin 17A (IL-17A) activity leads to a protumor microenvironment, dependent on its ability to induce the production of inflammatory mediators, mobilize myeloid cells and reshape the tumor environment. In the present study, we aimed to investigate the role of IL-17A in resistance to antitumor immunity and to explore the feasibility of anti-IL-17A combined with anti-PD-1 therapy in MSS CRC murine models. The expression of programmed cell death-ligand 1 (PD-L1) and its regulation by miR-15b-5p were investigated in MSS CRC cell lines and tissues. The effects of miR-15b-5p on tumorigenesis and anti-PD-1 treatment sensitivity were verified both in vitro and in colitis-associated cancer (CAC) and APCmin/+ murine models. In vivo efficacy and mechanistic studies were conducted using antibodies targeting IL-17A and PD-1 in mice bearing subcutaneous CT26 and MC38 tumors. Evaluation of clinical pathological specimens confirmed that PD-L1 mRNA levels are associated with CD8+ T cell infiltration and better prognosis. miR-15b-5p was found to downregulate the expression of PD-L1 at the protein level, inhibit tumorigenesis and enhance anti-PD-1 sensitivity in CAC and APCmin/+ CRC models. IL-17A led to high PD-L1 expression in CRC cells through regulating the P65/NRF1/miR-15b-5p axis. Combined IL-17A and PD-1 blockade had efficacy in CT26 and MC38 tumors, with more cytotoxic T lymphocytes cells and fewer myeloid-derived suppressor cells in tumors. IL-17A increases PD-L1 expression through the p65/NRF1/miR-15b-5p axis and promotes resistance to anti-PD-1 therapy. Blocking IL-17A improved the efficacy of anti-PD-1 therapy in MSS CRC murine models. IL-17A might serve as a therapeutic target to sensitize patients with MSS CRC to ICI therapy.

The pro-survival IKK-related kinase IKKepsilon integrates LPS and IL-17A signaling cascades to promote Wnt-dependent tumor development in the intestine.

Cancer Res.

2016 Mar 15

Goktuna SI, Shostak K, Chau TL, Heukamp LC, Hennuy B, Duong HQ, Ladang A, Close P, Klevernic I, Olivier F, Florin A, Ehx G, Baron F, Vandereyken M, Rahmouni S, Vereecke L, Van Loo G, Büttner R, Greten F, Chariot A.
PMID: 26980769 | DOI: -

Constitutive Wnt signaling promotes intestinal cell proliferation but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the pro-inflammatory Ikk-related kinase Ikkε in Wnt-driven tumor development. We found that Ikkε was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkε in β-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkε to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. Additionally, Ikkε was also required for lipopolysaccharide (LPS) and IL-17A-induced activation of Akt, Mek1/2, Erk1/2 and Msk1. Accordingly, genes encoding pro-inflammatory cytokines, chemokines and anti-microbial peptides were downregulated in Ikkε-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL-17A synthesis. Further studies revealed that IL-17A synergized with commensal bacteria to trigger Ikkε phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS and IL-17A-dependent signaling pathways converge on Ikkε to promote cell survival and establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation.βε.

IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice

Neuron

2021 Jul 01

Luo, X;Chen, O;Wang, Z;Bang, S;Ji, J;Lee, S;Huh, Y;Furutani, K;He, Q;Tao, X;Ko, M;Bortsov, A;Donnelly, C;Chen, Y;Nackley, A;Berta, T;Ji, R;
| DOI: 10.1016/j.neuron.2021.06.015

Although sex dimorphism is increasingly recognized as an important factor in pain, female-specific pain signaling is not well studied. Here we report that administration of IL-23 produces mechanical pain (mechanical allodynia) in female but not male mice, and chemotherapy-induced mechanical pain is selectively impaired in female mice lacking Il23 or Il23r. IL-23-induced pain is promoted by estrogen but suppressed by androgen, suggesting an involvement of sex hormones. IL-23 requires C-fiber nociceptors and TRPV1 to produce pain but does not directly activate nociceptor neurons. Notably, IL-23 requires IL-17A release from macrophages to evoke mechanical pain in females. Low-dose IL-17A directly activates nociceptors and induces mechanical pain only in females. Finally, deletion of estrogen receptor subunit α (ERα) in TRPV1+ nociceptors abolishes IL-23- and IL-17-induced pain in females. These findings demonstrate that the IL-23/IL-17A/TRPV1 axis regulates female-specific mechanical pain via neuro-immune interactions. Our study also reveals sex dimorphism at both immune and neuronal levels.

Immunity to the microbiota promotes sensory neuron regeneration

Cell

2023 Jan 06

Enamorado, M;Kulalert, W;Han, SJ;Rao, I;Delaleu, J;Link, VM;Yong, D;Smelkinson, M;Gil, L;Nakajima, S;Linehan, JL;Bouladoux, N;Wlaschin, J;Kabat, J;Kamenyeva, O;Deng, L;Gribonika, I;Chesler, AT;Chiu, IM;Le Pichon, CE;Belkaid, Y;
PMID: 36640762 | DOI: 10.1016/j.cell.2022.12.037

Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process.

Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients

Science immunology

2021 Feb 23

Zhao, Y;Kilian, C;Turner, JE;Bosurgi, L;Roedl, K;Bartsch, P;Gnirck, AC;Cortesi, F;Schultheiß, C;Hellmig, M;Enk, LUB;Hausmann, F;Borchers, A;Wong, MN;Paust, HJ;Siracusa, F;Scheibel, N;Herrmann, M;Rosati, E;Bacher, P;Kylies, D;Jarczak, D;Lütgehetmann, M;Pfefferle, S;Steurer, S;Zur-Wiesch, JS;Puelles, VG;Sperhake, JP;Addo, MM;Lohse, AW;Binder, M;Huber, S;Huber, TB;Kluge, S;Bonn, S;Panzer, U;Gagliani, N;Krebs, CF;
PMID: 33622974 | DOI: 10.1126/sciimmunol.abf6692

Hyperinflammation contributes to lung injury and subsequent acute respiratory distress syndrome (ARDS) with high mortality in patients with severe coronavirus disease 2019 (COVID-19). To understand the underlying mechanisms involved in lung pathology, we investigated the role of the lung-specific immune response. We profiled immune cells in bronchoalveolar lavage fluid and blood collected from COVID-19 patients with severe disease and bacterial pneumonia patients not associated with viral infection. By tracking T cell clones across tissues, we identified clonally expanded tissue-resident memory-like Th17 cells (Trm17 cells) in the lungs even after viral clearance. These Trm17 cells were characterized by a a potentially pathogenic cytokine expression profile of IL17A and CSF2 (GM-CSF). Interactome analysis suggests that Trm17 cells can interact with lung macrophages and cytotoxic CD8+ T cells, which have been associated with disease severity and lung damage. High IL-17A and GM-CSF protein levels in the serum of COVID-19 patients were associated with a more severe clinical course. Collectively, our study suggests that pulmonary Trm17 cells are one potential orchestrator of the hyperinflammation in severe COVID-19.

The pro-survival IKK-related kinase IKKepsilon integrates LPS and IL-17A signaling cascades to promote Wnt-dependent tumor development in the intestine

Cancer Res.

2016 May 01

Göktuna SI, Shostak K, Chau TL, Heukamp LC, Hennuy B, Duong HQ, Ladang A, Close P, Klevernic I, Olivier F, Florin A, Ehx G, Baron F, Vandereyken M, Rahmouni S, Vereecke L, van Loo G, Büttner R, Greten FR, Chariot A.
PMID: 26980769 | DOI: 10.1158/0008-5472.CAN-15-1473

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkε in Wnt-driven tumor development. We found that Ikkε was activated in intestinal tumors forming upon loss of the tumor suppressor Apc Genetic ablation of Ikkε in β-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkε to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkε was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding pro-inflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkε-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkε phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkε to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation.

	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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Probes for IL-17A

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Advanced Cell Diagnostics

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