From allergy to oncology: Targeting IL‐4 to boost cancer immunotherapy

Cancer can shape the tumor microenvironment (TME) by activating immune suppressive pathways. This discovery has led to the development of cancer immunotherapy drugs, which primarily target T lymphocytes and have been integrated into clinical practice over the past decade. Conversely, therapies targeting tumor-associated macrophages (TAMs) have, thus far, yielded disappointing results, likely due to a limited understanding of the underlying mechanisms of their ontogenesis.1 LaMarche et al.2 recently shed further light on the mechanisms of pro-tumorigenic myelopoiesis, revealing that this process is primarily orchestrated by the type 2 cytokine interleukin-4 (IL-4), and investigated the potential role of IL-4 inhibitors in a small cohort of patients with non-small cell lung cancer (NSCLC). Using a murine model and human samples of NSCLC, the authors demonstrated that a combination of cytokines derived from the TME (mainly IL-6, VEGF-A, and IL-18) synergistically stimulates bone marrow-resident basophils and eosinophils to produce IL-4. In turn, IL-4 in the bone marrow was found to reprogram the transcription of granulocyte-monocyte progenitors towards an immunosuppressive and tumorigenic phenotype (Figure 1A). Consistently, knock-out of the IL-4 receptor α (IL-4Rα) in mice with NSCLC significantly reduced tumor burden by reprogramming the TME towards an antitumor, inflamed state. Similar results were observed with basophil depletion, which abolished immunosuppressive myelopoiesis. Based on these findings, the authors translated their research into clinical practice by designing a phase 1b clinical trial for patients with relapsed/refractory NSCLC who had progressed on PD-1/PD-L1 blockade and had previously received chemotherapy and/or radiation. Checkpoint inhibitors, such as PD-1/PD-L1 blockers, have transformed cancer therapy by reactivating antitumoral immune responses, but less than half of NSCLC patients respond to these therapies, indicating a significant need for alternative treatments.2 In the study, the treatment regimen involved administration of the IL-4Rα antagonist dupilumab every 3 weeks, while maintaining PD-1/PD-L1 blocking. Dupilumab was given subcutaneously starting with a 600 mg loading dose, followed by 300 mg every 3 weeks for a total of three administrations. While no treatment-related adverse events were observed, dupilumab upregulated proinflammatory T helper 1-type cytokines (mainly IFNγ and IL-12), reduced circulating monocytes, and resulted in an expansion of plasma cells and effector CD8+ T cells (Figure 1B). This more proinflammatory shift corresponded to an impressive clinical benefit in one out of six included patients, who achieved a near-complete response after 9 months of treatment. Both the study's preclinical findings and preliminary clinical outcomes offer intriguing perspectives for cancer immunotherapy, which could be explored across various fronts. Firstly, the role of IL-4 in the TME must be extensively elucidated to define the clinical scenarios most likely to benefit from this approach. Recent evidence indicates that IL-4 may exhibit a more proinflammatory role, particularly when induced by PD-1/PD-L1 checkpoint inhibitors, by bolstering the CD8+ T cell response in the lymph nodes.3 Similarly, the TME response to various combinations of immunotherapy agents warrants comprehensive investigation. Compared to monotherapy, combined immunotherapy holds promise for greater efficacy in shifting the balance of TAMs toward proinflammatory populations. This fosters the recruitment and activity of effector T cells, through a positive feedback loop between T cells and TAMs that requires IFN-γ.4 The pivotal role of IFN-γ is consistent with the results of LaMarche et al.5 and with the experimental efficacy of CD4+ T cell-induced inflammatory cells in controlling immune-evasive tumors. Meanwhile, given the remarkable efficacy of combined therapy with dupilumab in NSCLC patients, it is plausible to hypothesize that targeted inhibition of IL-4 might represent just the tip of the iceberg in cancer immunotherapy. Beyond restructuring the TME, the combined therapeutic strategy proposed in this study holds promise for further application not only in NSCLC but also in other tumor types that are susceptible to immune checkpoint inhibitors. Finally, the discovery of this IL-4-mediated cancer-bone marrow axis involves other molecular players (such as JAK1 and STAT6) in the development of pro-tumorigenic myelopoiesis. These players can be inhibited by biologics and small molecules that are currently available or still under study,6 allowing us to speculate that the future battle against cancer will also involve the use of the therapeutic arsenal against atopic diseases, translating it from allergy to oncology. The authors would like to thank Dr. Mattia Giovannini for his invaluable advice and Dr. Anna Globinska for the final design of Figure 1. Open access publishing facilitated by Universita degli Studi di Milano, as part of the Wiley - CRUI-CARE agreement. This study was supported in part by funds from the "Current Research Annual Funding" of the Italian Ministry of Health. The authors declare that they have no conflict of interest to disclose in relation to this paper. None.