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The Immunosuppressive Niche of Soft-Tissue Sarcomas Is Sustained

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The Immunosuppressive Niche of Soft-Tissue Sarcomas Is Sustained Published OnlineFirst April 24, 2020; DOI: 10.1158/1078-0432.CCR-19-3416 CLINICAL CANCER RESEARCH | PRECISION MEDICINE AND IMAGING The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures A C Lingling Chen1, Teniola Oke1, Nicholas Siegel2, Gady Cojocaru3, Ada J. Tam1, Richard L. Blosser1, Jessica Swailes1, John A. Ligon1, Andriana Lebid4, Carol Morris5, Adam Levin5, Daniel S. Rhee6, Fabian M. Johnston7, Jonathan B. Greer7, Christian F. Meyer8, Brian H. Ladle1, Elizabeth D. Thompson9, Elizabeth A. Montgomery10, Woonyoung Choi11, David J. McConkey12, Robert A. Anders13, Drew M. Pardoll4, and Nicolas J. Llosa1 ABSTRACT ◥ Purpose: Clinical trials with immune checkpoint inhibition in bution diverged. UPS specimens demonstrated diffuse intratumoral sarcomas have demonstrated minimal response. Here, we interro- infiltration of T cells, while rhabdomyosarcomas samples revealed gated the tumor microenvironment (TME) of two contrasting soft- intratumoral T cells that clustered with B cells near perivascular tissue sarcomas (STS), rhabdomyosarcomas and undifferentiated beds, forming tertiary lymphoid structures (TLS). T cells in UPS þ pleomorphic sarcomas (UPS), with differing genetic underpinnings specimens were comprised of abundant CD8 T cells exhibiting and responses to immune checkpoint inhibition to understand the high PD-1 expression, which might represent the tumor reactive mechanisms that lead to response. repertoire. In rhabdomyosarcomas, T cells were limited to TLS, but Experimental Design: Utilizing fresh and formalin-fixed, par- expressed immune checkpoints and immunomodulatory molecules affin-embedded tissue from patients diagnosed with UPS and which, if appropriately targeted, could help unleash T cells into the rhabdomyosarcomas, we dissected the TME by using IHC, flow rest of the tumor tissue. cytometry, and comparative transcriptomic studies. Conclusions: Our work in STS revealed an immunosuppressive Results: Our results demonstrated both STS subtypes to be TME dominated by myeloid cells, which may be overcome with dominated by tumor-associated macrophages and infiltrated with activation of T cells that traffic into the tumor. In rhabdomyosar- immune cells that localized near the tumor vasculature. Both comas, targeting T cells found within TLS may be key to achieve subtypes had similar T-cell densities, however, their in situ distri- antitumor response. Introduction 1 Sarcomas are a heterogeneous group of bone and soft-tissue tumors Departement of Oncology, Johns Hopkins University School of Medicine and affecting both children and adults. In the realm of malignant soft-tissue Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD. 2Johns Hopkins University School of Medicine, Baltimore, MD. 3Discovery Research, Computa- sarcomas (STS), the most prevalent types are undifferentiated pleo- tional Research & Development, Compugen Ltd. 4Division of Immunology and morphic sarcomas (UPS) in adults and rhabdomyosarcomas in chil- Hematopoiesis, Department of Oncology, Johns Hopkins University School of dren (1). Both diseases are deforming and difficult to treat with poor Medicine, Baltimore, MD. 5Department of Orthopaedic Surgery and Oncology, 5-year survival outcomes of 52%–62% in patients with high-grade Johns Hopkins University, Baltimore, MD. 6Department of Pediatric Surgery, – 7 UPS, and 60% in patients with rhabdomyosarcoma (1 4). There are Johns Hopkins University, Baltimore, MD. Department of Surgical Oncology, several subtypes of rhabdomyosarcoma. The two most common Johns Hopkins University School of Medicine, Baltimore, MD. 8Department of Medical Oncology, The Johns Hopkins Sidney Kimmel Comprehensive Cancer subtypes affecting patients are alveolar (ARMS) and embryonal Center, Baltimore, MD. 9Department of Pathology, Johns Hopkins University (ERMS) rhabdomyosarcoma. ARMS occurs more commonly in ado- School of Medicine, Baltimore, MD. 10Department of Gastrointestinal and Liver lescents with tumor cells containing the characteristic chromosomal Pathology, Johns Hopkins University, Baltimore, MD. 11Department of Urology, translocations t(2;13) or t(1;13), and are commonly referred to as 12 Johns Hopkins University School of Medicine, Baltimore, MD. The Greenberg “fusion positive” rhabdomyosarcoma. ERMS occurs mainly in youn- Bladder Cancer Institute, Johns Hopkins School of Medicine, Baltimore, MD. ger children, carries a better prognosis, is characterized by LOH at 13Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD. 11p15 locus, and does not carry any characteristic chromosomal translocations, thus being termed “fusion negative” rhabdomyosar- Note: Supplementary data for this article are available at Clinical Cancer coma (1, 3, 5). For the past four decades, the backbone of sarcoma Research Online (http://clincancerres.aacrjournals.org/). therapy has been unchanged, consisting of surgery, radiation, and Corresponding Author: Nicolas J. Llosa, Johns Hopkins University School cytotoxic drugs. Improvement in survival outcomes have come to a of Medicine and Sidney Kimmel Comprehensive Cancer Center, CRB-I Room 4M-55, 1650, 0rleans street, Baltimore, MD 21287. Phone: 410-502-8104; standstill (5). Fax: 443-287-4653; E-mail: [email protected] The breakthrough of chimeric antigen receptor T cells in pre B-cell acute lymphoblastic leukemia and checkpoint inhibitors in melanoma, Clin Cancer Res 2020;XX:XX–XX non–small cell lung cancer, and numerous other solid tumor types, are doi: 10.1158/1078-0432.CCR-19-3416 the exemplar of successful immunotherapy and its potential to be Ó2020 American Association for Cancer Research. utilized for all tumors (6). Immunotherapy in sarcomas has thus far AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst April 24, 2020; DOI: 10.1158/1078-0432.CCR-19-3416 Chen et al. The objective of our work was to perform an in depth interrogation Translational Relevance of the immunobiology of prototypic STS with the goal of identifying Treatment paradigm for sarcomas has been unchanged for the immunotherapy agents that would match the immune characteristics past four decades with survival outcomes plateauing and patients of specific TMEs, thus providing more precise treatments for indi- with HR disease facing an abysmal prognosis. SARC028, trial vidual patients and cancer types. We specifically concentrated on UPS testing pembrolizumab in soft-tissue sarcoma, demonstrated and rhabdomyosarcoma given their prevalence and more importantly responses in undifferentiated pleomorphic sarcomas (UPS) and their contrasting biology and response to immune checkpoint block- dedifferentiated liposarcomas. Alliance A091401, trial combining ade (ICB), UPS is one of the few sarcomas that have shown complete ipilimumab and nivolumab, showed responses in more histologies, responses to checkpoint inhibition, while rhabdomyosarcoma shows but overall survival rates similar to standard chemotherapy. Here, no response whatsoever (18–20). Our in-depth comparison of these we compare the immune tumor microenvironment of two molec- two TMEs revealed a similar immune niche that was dependent on ularly distinct sarcomas: the genetically complex, immune check- angiogenesis and predominated by myeloid cells, but differed in their point responsive (ICR), UPS, and the genetically simple, fusion- spatial distribution of immune cells with UPS characterized by diffuse driven, poorly ICR, rhabdomyosarcoma, to identify factors that infiltration of T cells and rhabdomyosarcoma marked by T cells may contribute to their immunotherapy responsiveness. These two clustered in tertiary lymphoid structures (TLS). These differing char- subtypes represent the main genomic aberrancies observed in acteristics may be key to understanding tumor immunity in patients sarcomas. Results show both tumors are dominated by tumor- with STS. associated macrophages (TAM). T cells in UPS are diffusely distributed, while T cells in rhabdomyosarcomas cluster with B cells near perivascular beds forming tertiary lymphoid structure. Materials and Methods Our findings suggest targeting the myeloid compartment and Patient selection and tumor samples tumor angiogenesis could overcome the immunosuppressive niche Tumor tissue was collected at the Johns Hopkins Hospital (Balti- sustained by TAMs and lead to potential therapeutic targets. more, MD) from patients with UPS, ERMS, ARMS, and leiomyosar- coma. This study was conducted in accordance with the ethical principles stated in the Belmont Report and the U.S. Common Rule. It was approved by the Johns Hopkins Institutional Review Board had limited success. Trials in patients with osteosarcoma with (Baltimore, MD) and all samples were obtained in accordance with the high dose IL2, IFNa, and immunomodulatory agent muramyl tripep- Health Insurance and Accountability Act. This study was conducted tide have not yielded statistically significant responses (7–12). Simi- under an institutional review board–approved protocol with a waiver larly, vaccines with peptides spanning fusion genes unique to specific of consent. sarcoma subtypes, including SYT-SSX in synovial sarcoma, EWS/FLI- 1 in Ewing Sarcoma, and PAX3/FKHR (now known as PAX3/FOXO1) IHC analysis in ARMS, have mainly been ineffective (13–15). In patients with Formalin-fixed, paraffin-embedded (FFPE) tissue blocks from 39 synovial sarcoma,
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