The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures

Lingling Chen, Teniola Oke, Nicholas Siegel, Gady Cojocaru, Ada J. Tam, Richard L. Blosser, Jessica Swailes, John A. Ligon, Andriana Lebid, Carol Morris, Adam Levin, Daniel S. Rhee, Fabian M. Johnston, Jonathan B. Greer, Christian F. Meyer, Brian H. Ladle, Elizabeth D. Thompson, Elizabeth A. Montgomery, Woonyoung Choi, David J. McConkeyRobert A. Anders, Drew M. Pardoll, Nicolas J. Llosa

Research output: Contribution to journalArticle

Abstract

PURPOSE: Clinical trials with immune checkpoint inhibition in sarcomas have demonstrated minimal response. Here, we interrogated the tumor microenvironment (TME) of two contrasting soft-tissue sarcomas (STS), rhabdomyosarcomas and undifferentiated pleomorphic sarcomas (UPS), with differing genetic underpinnings and responses to immune checkpoint inhibition to understand the mechanisms that lead to response. EXPERIMENTAL DESIGN: Utilizing fresh and formalin-fixed, paraffin-embedded tissue from patients diagnosed with UPS and rhabdomyosarcomas, we dissected the TME by using IHC, flow cytometry, and comparative transcriptomic studies. RESULTS: Our results demonstrated both STS subtypes to be dominated by tumor-associated macrophages and infiltrated with immune cells that localized near the tumor vasculature. Both subtypes had similar T-cell densities, however, their in situ distribution diverged. UPS specimens demonstrated diffuse intratumoral infiltration of T cells, while rhabdomyosarcomas samples revealed intratumoral T cells that clustered with B cells near perivascular beds, forming tertiary lymphoid structures (TLS). T cells in UPS specimens were comprised of abundant CD8+ T cells exhibiting high PD-1 expression, which might represent the tumor reactive repertoire. In rhabdomyosarcomas, T cells were limited to TLS, but expressed immune checkpoints and immunomodulatory molecules which, if appropriately targeted, could help unleash T cells into the rest of the tumor tissue. CONCLUSIONS: Our work in STS revealed an immunosuppressive TME dominated by myeloid cells, which may be overcome with activation of T cells that traffic into the tumor. In rhabdomyosarcomas, targeting T cells found within TLS may be key to achieve antitumor response.

Original languageEnglish (US)
Pages (from-to)4018-4030
Number of pages13
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume26
Issue number15
DOIs
StatePublished - Aug 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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