The innate power of PD-1 blockade

Group 2 innate lymphoid cells (ILC2s) comprise a small proportion of the tumor microenvironment (TME) in a variety of solid tumors. Both pro- and anti-tumor effects have been attributed to ILCs, although their effects have not been systematically studied in melanoma.

Using multiplex immunohistochemistry, Jacquelot et al. confirmed the presence of multiple subsets of ILCs, including ILC2 and eosinophils, in human melanomas and recapitulated these findings in the murine Ret melanoma model. Genomic analysis of the metastatic melanoma samples from patients and Cox regression analyses showed that enrichment of ILC2s in the TME correlated with an increase in overall survival for individuals with metastatic disease.

Mechanistically evaluating these findings in murine preclinical models, the authors noted increase in tumor growth when ILC2-inactivated conditional knockout mice were inoculated with Ret melanoma cells as compared with control mice. Adoptive transfer of bone-marrow-derived ILC2 progenitors, α-lymphoid progenitors, and common lymphoid progenitors into ILC2-deficient Rag2^–/–Il2rγ^–/–mice confirmed that ILC2s mediated antitumor activity is independent of other lymphoid subsets.

Using scRNA sequencing of tumor-infiltrating leukocytes, the authors demonstrated that the ILC2-mediated antitumor response was driven by GM-CSF production and associated eosinophil infiltration of the TME. Deletion of PD-1 on ILC2s by reconstituting Rag2^–/–Il2rγ^–/–mice with Pdcd1^–/– bone marrow maximally impeded melanoma tumor growth. IL-33 stimulation of ILC2 expansion resulted in increased PD-1 expression on ILC2s, which the authors postulated could inhibit their anti-tumor function. Combinatorial therapy with IL-33 and PD-1 blockade in the Ret melanoma model significantly increased tumor-infiltrating ILC2s and eosinophils, which positively correlated with reduced tumor growth.

These studies unearth the potential of ILC2s in innate tumor immunotherapy. ILC2 expansion with IL-33 and PD-1 blockade poses a novel mechanism to achieve a sustained anti-tumor response in metastatic melanoma, an aggressive solid tumor with limited therapeutic options.

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