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CTLA-4 blockade induces a microglia-Th1 cell partnership that stimulates microglia phagocytosis and anti-tumor
Dan Chen1, Siva Karthik Varanasi1, Toshiro Hara2
1NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Abstract:
The limited efficacy of immunotherapies against glioblastoma underscores the urgency of better understanding immunity in the central nervous system. We found that treatment with αCTLA-4, but not αPD-1, prolonged survival in a mouse model of mesenchymal-like glioblastoma. This effect was lost upon the depletion of CD4+ T cells but not CD8+ T cells. αCTLA-4 treatment increased frequencies of intratumoral IFNγ-producing CD4+ T cells, and IFNγ blockade negated the therapeutic impact of αCTLA-4. The anti-tumor activity of CD4+ T cells did not require tumor-intrinsic MHC-II expression but rather required conventional dendritic cells as well as MHC-II expression on microglia. CD4+ T cells interacted directly with microglia, promoting IFNγ-dependent microglia activation and phagocytosis via the AXL/MER tyrosine kinase receptors, which were necessary for tumor suppression. Thus, αCTLA-4 blockade in mesenchymal-like glioblastoma promotes a CD4+ T cell-microglia circuit wherein IFNγ triggers microglia activation and phagocytosis and microglia in turn act as antigen-presenting cells fueling the CD4+ T cell response.
Insights
Anti-CTLA-4 immunotherapy improves survival in glioblastoma by activating CD4+ T cells. These T cells then engage microglia, enhancing their phagocytic activity and anti-tumor response.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Research
Background:
- Glioblastoma (GBM) exhibits limited response to current immunotherapies.
- Understanding central nervous system (CNS) immunity is critical for improving GBM treatment.
Purpose of the Study:
- To investigate the efficacy of anti-CTLA-4 and anti-PD-1 immunotherapies in a mesenchymal-like glioblastoma mouse model.
- To elucidate the role of CD4+ T cells, IFNγ, and microglia in the anti-tumor response mediated by anti-CTLA-4 therapy.
Main Methods:
- Treatment of mesenchymal-like glioblastoma-bearing mice with anti-CTLA-4 or anti-PD-1 antibodies.
- Depletion of CD4+ or CD8+ T cells to assess their role in therapeutic efficacy.
- Analysis of intratumoral cytokine production (IFNγ) and T cell populations.
- Investigation of MHC-II expression on tumor cells and antigen-presenting cells (APCs).
- Assessment of microglia activation, phagocytosis, and interaction with T cells.
Main Results:
- Anti-CTLA-4 therapy, but not anti-PD-1, significantly prolonged survival in the glioblastoma model.
- The survival benefit of anti-CTLA-4 was dependent on CD4+ T cells and IFNγ production.
- IFNγ blockade abrogated the therapeutic effect of anti-CTLA-4.
- Anti-tumor activity required microglia expressing MHC-II and conventional dendritic cells, not tumor-intrinsic MHC-II.
- CD4+ T cells activated microglia via IFNγ signaling through AXL/MER tyrosine kinase receptors, enhancing microglia phagocytosis.
Conclusions:
- Anti-CTLA-4 blockade is a promising immunotherapy for mesenchymal-like glioblastoma.
- The therapeutic mechanism involves a CD4+ T cell-microglia circuit, where IFNγ-activated microglia enhance phagocytosis and present antigens, thereby boosting the T cell response.
- Targeting this CD4+ T cell-microglia axis represents a novel strategy for glioblastoma treatment.
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