Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas
| Autor: | Steve W Thorpe, William J. Murphy, Ian R. Sturgill, Kevin Stoffel, Alicia A. Gingrich, Sean J. Judge, Logan V Vick, Robert J. Canter, Yue Lyu, May Cho, Robert B. Rebhun, Edmond F O'Donnell, Cordelia Dunai, Alyssa Bellini, Arta M. Monjazeb, Shuai Chen, Morgan A. Darrow |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cancer Research Lymphocyte medicine.medical_treatment killer cells 0302 clinical medicine Immunology and Allergy Cytotoxic T cell 2.1 Biological and endogenous factors Lymphocytes Prospective Studies Aetiology RC254-282 Cancer Clinical/Translational Cancer Immunotherapy Interleukin-15 Neoplasms. Tumors. Oncology. Including cancer and carcinogens Sarcoma Killer Cells Natural medicine.anatomical_structure Oncology Interleukin 15 030220 oncology & carcinogenesis Natural Molecular Medicine Female immunotherapy Pediatric Research Initiative combined modality therapy T cell Immunology 03 medical and health sciences Lymphocytes Tumor-Infiltrating Dogs TIGIT Clinical Research medicine innate Animals Humans Tumor-Infiltrating natural Pharmacology business.industry Immunotherapy immunity cytokines Blockade 030104 developmental biology Good Health and Well Being Cancer research business Ex vivo |
| Zdroj: | Journal for immunotherapy of cancer, vol 8, iss 2 Journal for ImmunoTherapy of Cancer, Vol 8, Iss 2 (2020) Journal for Immunotherapy of Cancer |
| Popis: | PurposeGiven the unmet need for novel immunotherapy in soft tissue sarcoma (STS), we sought to characterize the phenotype and function of intratumoral natural killer (NK) and T cells to identify novel strategies to augment tumor-infiltrating lymphocyte (TIL) function.Experimental designUsing prospectively collected specimens from dogs and humans with sarcomas, archived specimens, and The Cancer Genome Atlas (TCGA) data, we evaluated blood and tumor NK and T cell phenotype and function and correlated those with outcome. We then assessed the effects of interleukin 15 (IL-15) stimulation on both NK and T cell activation and TIGIT upregulation. Finally, we evaluated cytotoxic effects of IL-15 combined with TIGIT blockade using a novel anti-TIGIT antibody.ResultsTILs were strongly associated with survival outcome in both archived tissue and TCGA, but higher TIL content was also associated with higher TIGIT expression. Compared with blood, intratumoral NK and T cells showed significantly higher expression of both activation and exhaustion markers, in particular TIGIT. Ex vivo stimulation of blood and tumor NK and T cells from patients with STS with IL-15 further increased both activation and exhaustion markers, including TIGIT. Dogs with metastatic osteosarcoma receiving inhaled IL-15 also exhibited upregulation of activation markers and TIGIT. Ex vivo, combined IL-15 and TIGIT blockade using STS blood and tumor specimens significantly increased cytotoxicity against STS targets.ConclusionIntratumoral NK and T cells are prognostic in STS, but their activation is marked by significant upregulation of TIGIT. Our data suggest that combined IL-15 and TIGIT blockade may be a promising clinical strategy in STS. |
| Databáze: | OpenAIRE |
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