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

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

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  • Media type: E-Article
  • Title: The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures
  • Contributor: Chen, Lingling; Oke, Teniola; Siegel, Nicholas; Cojocaru, Gady; Tam, Ada J.; Blosser, Richard L.; Swailes, Jessica; Ligon, John A.; Lebid, Andriana; Morris, Carol; Levin, Adam; Rhee, Daniel S.; Johnston, Fabian M.; Greer, Jonathan B.; Meyer, Christian F.; Ladle, Brian H.; Thompson, Elizabeth D.; Montgomery, Elizabeth A.; Choi, Woonyoung; McConkey, David J.; Anders, Robert A.; Pardoll, Drew M.; Llosa, Nicolas J.
  • Published: American Association for Cancer Research (AACR), 2020
  • Published in: Clinical Cancer Research, 26 (2020) 15, Seite 4018-4030
  • Language: English
  • DOI: 10.1158/1078-0432.ccr-19-3416
  • ISSN: 1557-3265; 1078-0432
  • Origination:
  • Footnote:
  • Description: 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.
  • Access State: Open Access