IMMU-43 - CXCR3 signaling engages glioma infiltrating T cells and is required for the antitumor efficacy of innate stimulating immunotherapy

Background:  T cell dysfunction is well documented in patients with gliomas, yet mechanisms explaining T cell dysfunction in gliomas are lacking. Recent evidence links CXCR3 signaling and functional immune surveillance in both preclinical models and human data sets.

Methods:  Bulk and single cell RNA-seq data sets were used to compare CXCR3 ligand expression in gliomas to that of other solid tumor types. The role of CXCR3 signaling in mediating the recruitment and phenotype of tumor infiltrating lymphocytes (TILs) was tested using CXCR3 blockade and genetic deletion of CXCR3 in murine tumor models. The capacity of relevant innate stimulating immunotherapies to induce CXCR3 ligands in human glioma tissue was assessed using an ex vivo glioma slice culture assay, and the contribution of CXCR3 signaling to polio virotherapy (PVSRIPO) and STING agonist therapy was tested in murine models.

Results: Relative to other solid tumors, gliomas express significantly lower levels of CXCR3 ligands (CXCL9, 10, and 11), which are largely expressed by tumor associated myeloid cells. Blocking CXCR3 signaling profoundly restricted TIL recruitment in murine gliomas, and resulted in decreased TIL stemness features coinciding with exacerbated exhaustion phenotypes. Polio virotherapy and STING agonism efficiently induced CXCR3 ligand production in fresh human glioma tissue in a manner dependent upon myeloid cells, and at levels similar to that induced by the same agents in melanoma and breast cancer tissue. CXCR3+ TILs expressed higher levels of memory and activation markers, proliferated more, and were required for the antitumor efficacy of both polio virotherapy and a STING agonist in mice.

Conclusion: This work indicates that CXCR3 signaling, a key contributor to cancer immune surveillance, is disrupted in human gliomas relative to other solid tumor types. Intratumor virotherapy and STING agonists hold potential to rectify diminished CXCR3 ligand expression in gliomas.