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Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Ra antibody, is required to broadly inhibit type 2 inflammation

ABSTRACT: Background: Dupilumab, a fully human monoclonal antibody that binds IL-4Ra and inhibits signaling of both IL-4 and IL-13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL-4 and IL-13 in type 2 inflammation and report dupilumab mechanisms of action. Methods: Using primary cell assays and a mouse model of house dust mite induced asthma, we compared IL-4 versus IL-13 versus IL-4Ra blockers. Results: Intranasal administration of either IL-4 or IL-13 confers an asthma-like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head to head studies, either IL-4 or IL-13 inhibition to dual IL-4/IL-13 inhibition, we demonstrate that blockade of both IL-4 and IL-13 is required to broadly block type 2 inflammation, which translates to protection from allergen-induced lung function impairment. Notably, only dual IL-4/IL-13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils contribute to disease pathology. Conclusions: Overall, these data support IL-4 and IL-13 as key drivers of type 2 inflammation, and help provide insight into the therapeutic mechanism of dupilumab, a dual IL-4/IL-13 blocker, in multiple type 2 diseases.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE140900 | GEO | 2019/11/25

REPOSITORIES: GEO

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Project description:Myeloid cells, in particular monocytes and macrophages, are well-described to suppress the antitumor immune response. However, the molecular mechanisms controlling immunosuppressive myeloid cell states are ill- defined, hampering the development of myeloid-targeted therapies for cancer1,2. Here, we transcriptionally profiled over 500,000 tumor infiltrating leukocytes in non-small cell lung cancer (NSCLC) patients and in the KrasG12DTp53-/- (KP) murine lung adenocarcinoma model. In both species, the Type 2 cytokine IL-4 was predicted to be the primary driver of tumor infiltrating monocyte-derived macrophage (mo-mac) phenotype, despite the fact that lung tumors were largely devoid of IL-4 producing cells. Using a panel of conditional knockout mice, we found that only deletion of IL-4Ra within early myeloid progenitors in bone marrow (BM) reduced lung tumor burden, while deletion of this receptor in downstream mature myeloid cells had no effect. Detailed transcriptional analysis followed by mechanistic studies in vivo revealed an essential role for local BM IL-4 signaling in reprograming myelopoiesis in cancer. Mechanistically, basophils and eosinophils within BM upregulated IL4 production upon sensing distal tumor cues; local BM IL-4 acted on granulocyte-monocyte progenitors to transcriptionally program the development of immunosuppressive myeloid cells, which then homed to the tumor and promoted tumor growth. Consequentially, specific depletion of basophils, which were enriched in BM but absent from the tumor, profoundly reduced tumor burden and normalized myelopoiesis in experimental lung tumors. Prompted by these results, we designed and initiated the first clinical trial of dupilumab, a humanized IL- 4Ra blocking antibody commonly used for atopic disease, given in conjunction with PD-(L)1 blockade in relapsed/refractory NSCLC patients who had progressed on standard chemoimmunotherapy combinations. Consistent with our preclinical mouse data, dupilumab drove a reduction in circulating monocytes. This was coupled with an expansion of circulating and tumor-infiltrating CD8 T cells. Notably, one out of the six patients who enrolled in Phase 1b of this trial exhibited significant decrease in his tumor burden after two months of dupilumab treatment, and the clinical response deepened further to a near complete response even after cessation of dupilumab, suggestive of successful reprogramming of the antitumor response. Collectively, our study defines a role for IL-4 signaling in lung tumor progression, identifies a central axis controlling immunosuppressive myelopoiesis in cancer, and highlights a novel combination therapy for immune checkpoint blockade in humans.

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Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Ra antibody, is required to broadly inhibit type 2 inflammation

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