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Pathways of Immune Exclusion in Metastatic Osteosarcoma Are Associated with Inferior Patient Outcomes

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Pathways of Immune Exclusion in Metastatic Osteosarcoma Are Associated with Inferior Patient Outcomes Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-001772 on 21 May 2021. Downloaded from Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes 1,2 3 3 1 John A Ligon , Woonyoung Choi, Gady Cojocaru, Wei Fu, 4 1 1 3 Emily Han- Chung Hsiue, Teniola F Oke, Nicholas Siegel, Megan H Fong , Brian Ladle,1 Christine A Pratilas,1 Carol D Morris,5 Adam Levin,5 Daniel S Rhee,6 Christian F Meyer,1 Ada J Tam,1 Richard Blosser,1 Elizabeth D Thompson,7 Aditya Suru,1 David McConkey,3 Franck Housseau,1 Robert Anders,7 1 1 Drew M Pardoll, Nicolas Llosa To cite: Ligon JA, Choi W, ABSTRACT Conclusions Osteosarcoma PMs exhibit immune Cojocaru G, et al. Pathways of Background Current therapy for osteosarcoma exclusion characterized by the accumulation of TILs at immune exclusion in metastatic pulmonary metastases (PMs) is ineffective. The the PM interface. These TILs produce effector cytokines, osteosarcoma are associated mechanisms that prevent successful immunotherapy suggesting their capability of activation and recognition with inferior patient outcomes. in osteosarcoma are incompletely understood. We of tumor antigens. Our findings suggest cooperative Journal for ImmunoTherapy immunosuppressive mechanisms in osteosarcoma PMs of Cancer 2021;9:e001772. investigated the tumor microenvironment of metastatic doi:10.1136/jitc-2020-001772 osteosarcoma with the goal of harnessing the immune including immune checkpoint molecule expression and the system as a therapeutic strategy. presence of immunosuppressive myeloid cells. We identify Methods 66 osteosarcoma tissue specimens were cellular and molecular signatures that are associated with ► Additional supplemental material is published online only. analyzed by immunohistochemistry (IHC) and immune patient outcomes, which could be exploited for successful To view, please visit the journal markers were digitally quantified. Tumor-infiltra ting immunotherapy. online (http:// dx. doi. org/ 10. lymphocytes (TILs) from 25 specimens were profiled 1136/ jitc- 2020- 001772). by functional cytometry. Comparative transcriptomic studies of distinct tumor- normal lung ‘PM interface’ BACKGROUND Accepted 10 February 2021 and ‘PM interior’ regions from 16 PMs were performed. Osteosarcoma is the most common bone Clinical follow-up (median 24 months) was available from 1 resection. malignancy in children and young adults. Results IHC revealed a statistically significantly higher While patients with localized disease have a http://jitc.bmj.com/ concentration of TILs expressing immune checkpoint cure rate approaching 70%, patients who and immunoregulatory molecules in PMs compared with develop metastatic disease have a 5- year overall primary bone tumors (including programmed cell death 1 survival of less than 25%,1 with most patients (PD-1), programmed death ligand 1 (PD- L1), lymphocyte- dying from pulmonary metastases (PMs).2 activation gene 3 (LAG-3), T-cell immunoglobulin Unfortunately, the treatment paradigm for and mucin domain- containing protein 3 (TIM-3), and osteosarcoma has remained unchanged for on September 28, 2021 by guest. Protected copyright. indoleamine 2,3-dioxygenase (IDO1). Remarkably, these approximately 30 years.3 Adjuvant chemo- lymphocytes are excluded at the PM interface compared therapy offers no benefit for patients who with PM interior. TILs from PMs exhibited significantly 4 higher amounts of PD-1 and LAG-3 and functional suffer metastatic relapse, and new classes cytokines including interferon-γ (IFNγ) by flow cytometry. of therapeutics are urgently needed for this Gene expression profiling further confirmed the presence chemotherapy- insensitive disease. of CD8 and CD4 lymphocytes concentrated at the PM Several pieces of evidence point to an interface, along with upregulation of immunoregulatory important role for the immune system in molecules and IFNγ-driven genes in the same region. the clearance of osteosarcoma,5 offering © Author(s) (or their We further discovered a strong alternatively activated hope that tumor immunotherapy could be employer(s)) 2021. Re- use macrophage signature throughout the entire PMs along successful in osteosarcoma as it has been for permitted under CC BY-NC. No with a polymorphonuclear myeloid-derived suppressor many types of cancer.6 Furthermore, loss of commercial re- use. See rights cell signature focused at the PM interface. Expression of and permissions. Published by human leukocyte antigen class 1 expression PD-L1, LAG-3, and colony-stimula ting factor 1 receptor BMJ. on tumor cells correlates with poor overall (CSF1R) at the PM interface was associated with For numbered affiliations see significantly worse progression-free survival (PFS), while survival in patients with osteosarcoma, end of article. gene sets indicative of productive T cell immune responses suggesting that evading immune recogni- (CD8 T cells, T cell survival, and major histocompatibility tion confers a survival advantage for tumor Correspondence to 7 Dr Nicolas Llosa; complex class 1 expression) were associated with cells. While immune- based therapies have nllosa1@ jhmi. edu significantly improved PFS. been successful in some sarcomas and other Ligon JA, et al. J Immunother Cancer 2021;9:e001772. doi:10.1136/jitc-2020-001772 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-001772 on 21 May 2021. Downloaded from pediatric cancers,8 9 these beneficial findings have not informed consent for prospective tumor collection. All been generalizable to many sarcomas, including osteosar- samples were obtained in accordance with the Health coma specifically.9–12 Insurance Portability and Accountability Act. While immunotherapy has not changed outcomes for patients with osteosarcoma, correlative findings Immunohistochemistry (IHC) and preclinical studies show that the tumor microen- Sixty- six formalin- fixed paraffin- embedded tissue blocks vironment (TME) of osteosarcoma can be altered.13–16 (28 untreated bone, 12 bone post- chemotherapy, 25 lung Rigorous understanding of the mechanisms regulating metastases, 1 soft tissue recurrence/metastasis) from 31 the tumor–immune system interface is a crucial prerequi- patients with osteosarcoma were cut into 5 µm sections site for rationally designed therapies to alter the TME in a and mounted onto glass slides. Each specimen was stained way that will allow immunotherapy to be effective in osteo- for H&E according to standard protocols, and for CD3, sarcoma. The TME of any cancer has different systems to CD8, Foxp3, CD163, programmed cell death 1 (PD-1), prevent recognition and attack by the immune system, and PD-L1 per online supplemental table 1). Additional and instead promote tolerance,17 thus allowing tumor staining for colony- stimulating factor 1 receptor (CSF1R), progression. Understanding the TME in PMs is crucial, T- cell immunoglobulin and mucin domain- containing and analyses derived from study of these specimens protein 3 (TIM-3), lymphocyte- activation gene 3 (LAG-3) have resulted in controversial conclusions. One recent and indoleamine 2,3-dioxygenase (IDO1) was performed paper suggests that vascular dysfunction in metastatic on osteosarcoma PMs (online supplemental table 11). osteosarcoma results in lower expression of a number of Whole slides were then digitally scanned to a magnification immune markers compared with primary tumors,18 while of 20x (Scanscope XT), analyzed (Halo imaging analysis contrasting reports show that metastatic lesions have a software; Indica Labs, Corrales, New Mexico, USA) and higher number of tumor-infiltrating lymphocytes (TILs), densities scored as cells/mm2 (CD3, CD8, Foxp3, CD163, higher expression of programmed death ligand 1 (PD- PD-1, LAG-3) or area percentage (PD-L1, CSF1R, TIM-3, L1), and are marked by a number of immunosuppres- IDO1). PD-L1 positivity was scored as a percentage of the sive mechanisms.19 20 Nevertheless, a deeper and more total tissue area, including both tumor and immune cells, granular understanding of the metastatic TME, partic- given the expression of PD- L1 on both cell populations in ularly the precise regional distribution and interplay of our samples. In PMs, the tumor-normal lung ‘interface’ immune cells along with the operative immunoregulatory (PM interface) region (when present in the available signaling programs, are greatly needed. slide) was defined as a 400 µm width region where the We hypothesized that (1) the TME of osteosarcoma tumor meets the lung tissue. Slides were reviewed with a PMs is significantly different from that of the primary pathologist (RA and EDT) to demarcate areas of tumor bone tumors, and (2) that a comprehensive analysis of versus normal tissue and to confirm our digital image the metastatic TME would reveal multifactorial determi- analysis. nants of osteosarcoma immune responsiveness. Herein, http://jitc.bmj.com/ we undertook an orthogonal interrogation approach Laser capture microdissection and RNA extraction for studying the TME of metastatic osteosarcoma, imple- Formalin- fixed paraffin- embedded tissue blocks and menting human tumor samples and freshly isolated H&E- stained tissue sections (10 µm, mounted using RNA TILs. Our analysis reveals that, compared with the rela- precautions) of 16 PMs were used for the laser capture tive ‘immune desert’ TME of primary bone tumors, the microdissection (Leica LMD 7000 system). For each TME of metastatic osteosarcoma represents the ‘immune- sample, tissues were microdissected from the
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