Selective targeting of IL2Rβγ combined with radiotherapy triggers CD8- and NK-mediated immunity, abrogating metastasis in HNSCC

Summary

The implementation of cancer immunotherapies has seen limited clinical success in head and neck squamous cell carcinoma (HNSCC). Interleukin-2 (IL-2), which modulates the survival and functionality of lymphocytes, is an attractive target for new immunotherapies but one that is limited by presence of regulatory T cells (Tregs) expressing the high-affinity IL-2Rα. The bispecific immunocytokine PD1-IL2v preferentially delivers IL-2 signaling through IL-2Rβγ on PD-1-expressing cells. Selectively targeting the intermediate-affinity IL-2Rβγ can be leveraged to induce anti-tumor immune responses in effector T cells and natural killer (NK) cells while limiting the negative regulation of IL-2Rα activation on Tregs. Using radiation therapy (RT) in combination with PD1-IL2v improves local tumor control and survival, and controls metastatic spread in orthotopic HNSCC tumor models. PD1-IL2v drives systemic activation and expansion of circulating and tumor-infiltrating cytotoxic T cells and NK cells while limiting Treg-mediated immunosuppression. These data show that PD1-L2v induces durable systemic tumor control in HNSCC.

Graphical abstract

Highlights

• •

  Combined RT and PD1-IL2v drives tumor regression and increases survival

• •

  RT + PD1-IL2v initiates tumor-reactive T cell responses while limiting Treg suppression

• •

  RT + PD1-IL2v enhances NK cell activating receptor expression and cytotoxicity

• •

  Improved NK immunosurveillance controls metastatic spread to lungs

Abstract

In aggressive models of head and neck cancer, Gadwa et al. demonstrate that radiation therapy combined with the immunocytokine PD1-IL2v elicits a robust anti-tumor immune response by invigorating T cell and natural killer cell activation and expansion across multiple immunological compartments, resulting in superior primary and distant tumor control.