Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas

Zohreh Amoozgar,Ana Batista,Hye-Jung Kim,Nancy Wang,Shanmugarajan Krishnan,Rong En Tay,Christina S.f Wong ,Émilie Mamessier ,Jessica M Posada,Dai Fukumura,Sylvie Roberge,Gino B Ferraro,Evgeny Kiner,Alex K Shalek,Mitrajit Ghosh,Jonas Kloepper,Jun Ren,Lei Xu,Peigen Huang,Samuel W Kazer,Mark Badeaux,Rakesh K Jain

doi:10.1038/s41467-021-22885-8

Abstract

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.

Highlights

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials
Because ICBs are designed to interfere with inhibitory pathways that limit T cell responses to tumors, we first determined the effect of αPD1 therapy on the T cell infiltrate in GL261-MGH
We found that in contrast to Treg cells from mice treated with IgG2a or αPD1 alone, Treg cells from mice treated with αGITR antibody or combined αPD1 + αGITR antibodies (Supplementary Fig. 8a) lost their ability to suppress CD8 T cell proliferation (Supplementary Fig. 8b), which increased the number of IFNγ-secreting

Summary

Introduction

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. ΑGITR treatment converts immunosuppressive Treg cells into anti-tumor Th1-like CD4 T cells and overcomes resistance to αPD1 in experimental GBMs. Here, using three preclinical murine models of GBM, we show that αGITR treatment converts the immunosuppressive TME of GBM into an immunostimulatory milieu by preferentially targeting GBM Treg cells. ΑGITR treatment converts immunosuppressive Treg cells into anti-tumor Th1-like CD4 T cells and overcomes resistance to αPD1 in experimental GBMs This strategy has several advantages over targeting CTLs. First, since the T-cell receptor (TCR) repertoire of Treg cells is skewed toward recognizing self-antigens[22], converted Treg cells can recognize self-antigens expressed by GBM tumor cells without requiring neoantigen epitopes as CTLs normally do. We evaluate if such a strategy can be effectively combined with the standard of care (SoC) therapy for newly diagnosed GBM1

Methods

Results

Conclusion