Surgery, University of California Davis School of Medicine, Sacramento, California, USA.
Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, California, USA.
J Immunother Cancer. 2020 Nov;8(2). doi: 10.1136/jitc-2020-001355.
Given 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.
Using 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.
TILs 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.
Intratumoral 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.
鉴于软组织肉瘤（STS）对新型免疫疗法的需求未得到满足，我们试图描述肿瘤内自然杀伤（NK）和 T 细胞的表型和功能，以确定增强肿瘤浸润淋巴细胞（TIL）功能的新策略。
使用来自患有肉瘤的狗和人类的前瞻性收集标本、存档标本和癌症基因组图谱（TCGA）数据，我们评估了血液和肿瘤 NK 和 T 细胞的表型和功能，并将其与结果相关联。然后，我们评估了白细胞介素 15（IL-15）刺激对 NK 和 T 细胞激活和 TIGIT 上调的影响。最后，我们使用新型抗 TIGIT 抗体评估了 IL-15 与 TIGIT 阻断联合的细胞毒性作用。
TIL 与存档组织和 TCGA 中的生存结果均密切相关，但更高的 TIL 含量也与更高的 TIGIT 表达相关。与血液相比，肿瘤内 NK 和 T 细胞表现出更高的激活和衰竭标志物表达，特别是 TIGIT。用 IL-15 对 STS 患者的血液和肿瘤 NK 和 T 细胞进行体外刺激进一步增加了激活和衰竭标志物，包括 TIGIT。接受吸入性 IL-15 的患有转移性骨肉瘤的狗也表现出激活标志物和 TIGIT 的上调。在体外，使用 STS 血液和肿瘤标本联合 IL-15 和 TIGIT 阻断显著增加了对 STS 靶标的细胞毒性。
肿瘤内 NK 和 T 细胞在 STS 中具有预后意义，但它们的激活标志着 TIGIT 的显著上调。我们的数据表明，联合使用 IL-15 和 TIGIT 阻断可能是 STS 的一种有前途的临床策略。
