Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas

Abstract

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.

Novel Insights into the Immunotherapy of Soft Tissue Sarcomas: Do We Need a Change of Perspective?

“…Hence, detailed analyses would be truly beneficial in STSs. While intratumoral NK cells of STSs exhibit numerous activation and exhaustion markers, peripheral NK cells in STS patients were observed as functionally impaired [86,87]. Patients undergoing NK-cell based immunotherapies mostly profit from administration of IL-15, a potent NK cell activator, while anti-NKG2A therapy is still lacking among clinical trials in STSs [125,126].…”

“…Judge et al further demonstrated that intratumoral NK cells express more activation and exhaustion markers as compared to peripheral blood NK cells [87]. Furthermore, ex vivo stimulation with IL-15 further increased both activation and exhaustion markers in intratumoral and peripheral blood NK cells [87]. The authors observed a significant upregulation of TIGIT receptor and, therefore, suggested a therapeutic potential of TIGIT blockade together with IL-15 therapy [87].…”

“…Bücklein et al have provided a detailed analysis of NK cell presence and function in STSs patients and, unlike in other malignancies, peripheral blood NK cells exhibited a profound impairment in cell function, especially in the intermediate and high-grade STSs [86]. Judge et al further demonstrated that intratumoral NK cells express more activation and exhaustion markers as compared to peripheral blood NK cells [87]. Furthermore, ex vivo stimulation with IL-15 further increased both activation and exhaustion markers in intratumoral and peripheral blood NK cells [87].…”

Design and Implementation of NK Cell-Based Immunotherapy to Overcome the Solid Tumor Microenvironment

“…Importantly, the therapeutic effect of TIGIT antibody blockade was found to be NK cell-dependent as antibody-mediated NK cell depletion in mice 24 h prior to TIGIT blockade abrogated the positive effects of TIGIT antibody treatment [ 104 ]. Similar studies in human peripheral blood NK cells showed that TIGIT blockade enhanced their anti-tumor activity against soft-tissue sarcoma and ovarian carcinoma tumor targets in vitro, and significantly, reduced tumor burden of mice with ovarian carcinoma xenografts [ 105 , 106 ]. These encouraging pre-clinical results have led to the initiation of multiple clinical trials using monoclonal anti-TIGIT antibodies alone or in combination with other checkpoint inhibitors (NCT02913313, NCT04570839].…”

Heterodimeric IL-15 in Cancer Immunotherapy

“…RLI also enhanced the anti-tumor activity of PD-1 antagonist [ 98 ]. TIGIT has emerged as an additional checkpoint inhibitor for novel combinatorial therapy with IL-15 [ 99 ].…”