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Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma

Author

Listed:
  • Alexander H. Lee

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Lu Sun

    (University of California, Los Angeles)

  • Aaron Y. Mochizuki

    (University of California, Los Angeles)

  • Jeremy G. Reynoso

    (University of California, Los Angeles)

  • Joey Orpilla

    (University of California, Los Angeles)

  • Frances Chow

    (University of California, Los Angeles)

  • Jenny C. Kienzler

    (University of California, Los Angeles)

  • Richard G. Everson

    (University of California, Los Angeles
    UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles)

  • David A. Nathanson

    (University of California, Los Angeles
    UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles)

  • Steven J. Bensinger

    (University of California, Los Angeles
    UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles
    University of California, Los Angeles)

  • Linda M. Liau

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles)

  • Timothy Cloughesy

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles)

  • Willy Hugo

    (UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles
    Parker Institute for Cancer Immunotherapy
    University of California, Los Angeles)

  • Robert M. Prins

    (University of California, Los Angeles
    University of California, Los Angeles
    UCLA Jonsson Comprehensive Cancer Center, University of California, Los Angeles
    Parker Institute for Cancer Immunotherapy)

Abstract

Primary brain tumors, such as glioblastoma (GBM), are remarkably resistant to immunotherapy, even though pre-clinical models suggest effectiveness. To understand this better in patients, here we take advantage of our recent neoadjuvant treatment paradigm to map the infiltrating immune cell landscape of GBM and how this is altered following PD-1 checkpoint blockade using high dimensional proteomics, single cell transcriptomics, and quantitative multiplex immunofluorescence. Neoadjuvant PD-1 blockade increases T cell infiltration and the proportion of a progenitor exhausted population of T cells found within the tumor. We identify an early activated and clonally expanded CD8+ T cell cluster whose TCR overlaps with a CD8+ PBMC population. Distinct changes are also observed in conventional type 1 dendritic cells that may facilitate T cell recruitment. Macrophages and monocytes still constitute the majority of infiltrating immune cells, even after anti-PD-1 therapy. Interferon-mediated changes in the myeloid population are consistently observed following PD-1 blockade; these also mediate an increase in chemotactic factors that recruit T cells. However, sustained high expression of T-cell-suppressive checkpoints in these myeloid cells continue to prevent the optimal activation of the tumor infiltrating T cells. Therefore, future immunotherapeutic strategies may need to incorporate the targeting of these cells for clinical benefit.

Suggested Citation

  • Alexander H. Lee & Lu Sun & Aaron Y. Mochizuki & Jeremy G. Reynoso & Joey Orpilla & Frances Chow & Jenny C. Kienzler & Richard G. Everson & David A. Nathanson & Steven J. Bensinger & Linda M. Liau & T, 2021. "Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26940-2
    DOI: 10.1038/s41467-021-26940-2
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    1. Seethalakshmi Hariharan & Benjamin T. Whitfield & Christopher J. Pirozzi & Matthew S. Waitkus & Michael C. Brown & Michelle L. Bowie & David M. Irvin & Kristen Roso & Rebecca Fuller & Janell Hostettle, 2024. "Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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