Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes

• DOI: 10.1136/jitc-2020-001772
• Publication Date: 2021-05-21T16:16:10Z
• Authors: John A Ligon; Woonyoung Choi; Gady Cojocaru; Wei Fu; Emily Han-Chung H...; Teniola F Oke; Nicholas Siegel; Megan H Fong; Brian Ladle; Christine A Pratilas; Carol D Morris; Adam Levin; Daniel S Rhee; Christian F Meyer; Ada J Tam; Richard Blosser; Elizabeth D Thompson; Aditya Suru; David McConkey; Franck Housseau; Robert Anders; Drew M Pardoll; Nicolas Llosa
• Keywords: Immune checkpoint; Tumor-infiltrating lymphocytes; Gene signature; Cancer Immunotherapy

Background Current therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in are incompletely understood. We investigated the tumor microenvironment of metastatic with goal harnessing immune system as a therapeutic strategy. Methods 66 tissue specimens were analyzed by immunohistochemistry (IHC) and markers digitally quantified. Tumor-infiltrating lymphocytes (TILs) from 25 profiled functional cytometry. Comparative transcriptomic studies distinct tumor-normal lung ‘PM interface’ interior’ regions 16 PMs performed. Clinical follow-up (median 24 months) was available resection. Results IHC revealed statistically significantly higher concentration TILs expressing checkpoint immunoregulatory molecules compared primary bone tumors (including programmed cell death 1 (PD-1), ligand (PD-L1), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin mucin domain-containing protein (TIM-3), indoleamine 2,3-dioxygenase (IDO1). Remarkably, these excluded at PM interface interior. exhibited amounts PD-1 LAG-3 cytokines including interferon-γ (IFNγ) flow Gene expression profiling further confirmed presence CD8 CD4 concentrated interface, along upregulation IFNγ-driven genes same region. discovered strong alternatively activated macrophage signature throughout entire polymorphonuclear myeloid-derived suppressor focused interface. Expression PD-L1, LAG-3, colony-stimulating factor receptor (CSF1R) associated worse progression-free survival (PFS), while sets indicative productive T responses (CD8 cells, survival, major histocompatibility complex class expression) improved PFS. Conclusions Osteosarcoma exhibit exclusion characterized accumulation These produce effector cytokines, suggesting their capability activation recognition antigens. Our findings suggest cooperative immunosuppressive molecule myeloid cells. identify cellular molecular signatures patient outcomes, which could be exploited immunotherapy.