期刊
JOURNAL FOR IMMUNOTHERAPY OF CANCER
卷 9, 期 5, 页码 -出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2020-001772
关键词
sarcoma; tumor microenvironment; pediatrics; translational medical research
资金
- Johns Hopkins Hospital, Bloomberg-Kimmel Institute for Immunotherapy
- Bloomberg Philanthropies
- St. Baldrick's foundation
- BMS II--ON
- National Pediatric Cancer Foundation
- Giant Food
The study found that osteosarcoma pulmonary metastases (PMs) exhibit immune exclusion with an accumulation of tumor-infiltrating lymphocytes at the PM interface, which produce effector cytokines. Additionally, there were alternatively activated macrophages and polymorphonuclear myeloid-derived suppressor cells in different distributions between the center and edge of the PMs. These findings suggest potential cooperative immunosuppressive mechanisms that could be targeted for successful immunotherapy.
Background Current therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in osteosarcoma are incompletely understood. We investigated the tumor microenvironment of metastatic osteosarcoma with the goal of harnessing the immune system as a therapeutic strategy. Methods 66 osteosarcoma tissue specimens were analyzed by immunohistochemistry (IHC) and immune markers were digitally quantified. Tumor-infiltrating lymphocytes (TILs) from 25 specimens were profiled by functional cytometry. Comparative transcriptomic studies of distinct tumor-normal lung 'PM interface' and 'PM interior' regions from 16 PMs were performed. Clinical follow-up (median 24 months) was available from resection. Results IHC revealed a statistically significantly higher concentration of TILs expressing immune checkpoint and immunoregulatory molecules in PMs compared with primary bone tumors (including programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and indoleamine 2,3-dioxygenase (IDO1). Remarkably, these lymphocytes are excluded at the PM interface compared with PM interior. TILs from PMs exhibited significantly higher amounts of PD-1 and LAG-3 and functional cytokines including interferon-gamma (IFN gamma) by flow cytometry. Gene expression profiling further confirmed the presence of CD8 and CD4 lymphocytes concentrated at the PM interface, along with upregulation of immunoregulatory molecules and IFN gamma-driven genes in the same region. We further discovered a strong alternatively activated macrophage signature throughout the entire PMs along with a polymorphonuclear myeloid-derived suppressor cell signature focused at the PM interface. Expression of PD-L1, LAG-3, and colony-stimulating factor 1 receptor (CSF1R) at the PM interface was associated with significantly worse progression-free survival (PFS), while gene sets indicative of productive T cell immune responses (CD8 T cells, T cell survival, and major histocompatibility complex class 1 expression) were associated with significantly improved PFS. Conclusions Osteosarcoma PMs exhibit immune exclusion characterized by the accumulation of TILs at the PM interface. These TILs produce effector cytokines, suggesting their capability of activation and recognition of tumor antigens. Our findings suggest cooperative immunosuppressive mechanisms in osteosarcoma PMs including immune checkpoint molecule expression and the presence of immunosuppressive myeloid cells. We identify cellular and molecular signatures that are associated with patient outcomes, which could be exploited for successful immunotherapy.
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