TY - JOUR
T1 - The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures
AU - Chen, Lingling
AU - Oke, Teniola
AU - Siegel, Nicholas
AU - Cojocaru, Gady
AU - Tam, Ada J.
AU - Blosser, Richard L.
AU - Swailes, Jessica
AU - Ligon, John A.
AU - Lebid, Andriana
AU - Morris, Carol
AU - Levin, Adam
AU - Rhee, Daniel S.
AU - Johnston, Fabian M.
AU - Greer, Jonathan B.
AU - Meyer, Christian F.
AU - Ladle, Brian H.
AU - Thompson, Elizabeth D.
AU - Montgomery, Elizabeth A.
AU - Choi, Woonyoung
AU - McConkey, David J.
AU - Anders, Robert A.
AU - Pardoll, Drew M.
AU - Llosa, Nicolas J.
N1 - Funding Information:
This work was supported by Johns Hopkins Hospital, Bloomberg-Kimmel Institute for Immunotherapy; Bloomberg Philanthropies, BMS II-ON, Pediatric Cancer Research Foundation, Rally Foundation, Infinite Love for Kids Fighting Cancer in memory of Mia Rose McCaffrey Forever 6, Open Hands Overflowing Hearts, and Giant Food.
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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 CD8þ 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.
AB - 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 CD8þ 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.
UR - http://www.scopus.com/inward/record.url?scp=85089128418&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85089128418&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-3416
DO - 10.1158/1078-0432.CCR-19-3416
M3 - Article
C2 - 32332015
AN - SCOPUS:85089128418
SN - 1078-0432
VL - 26
SP - 4018
EP - 4030
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -