The Role of Natural Killer Cells in Soft Tissue Sarcoma: Prospects for Immunotherapy

Abstract

Soft-tissue sarcomas (STS) represent about 80% of sarcomas, and are a heterogeneous group of rare and malignant tumors. STS arise from mesenchymal tissues and can grow into structures such as adipose tissue, muscles, nervous tissue and blood vessels. Morphological evaluation has been the standard model for the diagnosis of sarcomas, and even in samples with similar characteristics, they present a diversity in cytogenetic and genetic sequence alterations, which further increases the diversity of sarcomas. This variety is one of the main challenges for the classification and understanding of STS patterns, as well as for their respective treatments, which further decreases patient survival (<5 years). Despite some studies, little is known about the immunological profile of STS. As for the immunological profile of STS in relation to NK cells, there is also a shortage of studies. Observations made in solid tumors show that the infiltration of NK cells in tumors is associated with a good prognosis of the disease. Notwithstanding the scarcity of studies to characterize NK cells, their receptors, and ligands in STS, it is noteworthy that the progression of these malignancies is associated with altered NK phenotypes. Despite the scarcity of information on the function of NK cells, their phenotypes and their regulatory pathways in STS, the findings of this study support the additional need to explore NK cell-based immunotherapy in STS further. Some clinical trials, very tentatively, are already underway. STS clinical trials are still the basis for adoptive NK-cell and cytokine-based therapy.

Keywords: clinical trials; immune checkpoint inhibitors; immunotherapy; innate immunity; innate lymphoid cells; natural killer cells; soft tissue sarcoma.

Figure 1

Inhibitory and activatory receptors of NK cells and their ligands. The expression of activatory receptors (CD16, aKIRs, NKG2C, NKG2D, NKp30, NKp46, NKp44 and NKp80), co-activator receptors (DNAM-1, 2B4, NTBA) and their ligands activate the cytotoxic response and tumor lysis of NK cells. The expression of inhibitory receptors (iKIR, NKG2A, TIGIT, TACTILE/CD96, TIM-3, LAG-3, CTLA-4, PD-1 and PVRG) suppresses the NK cell response promoting tumor growth. The activation and the inhibition are determined by the interaction of these receptors and their ligands.

Figure 2

Antibody-based immunotherapy in STS. PD-1 and CTLA-4 are co-inhibitor receptors expressed by NK that can be blocked using immune checkpoint inhibitors: anti-PD-1 (pembrolizumab and nivolumab) and anti-CTLA-4 (ipilimumab and tremelizumab). PD-L1, a ligand of PD-1 expressed by tumor cells, can be blocked using anti-PD-L1 (avelumab, darvalumab e atezolizumab). iKIR and NKG2A, two specific NK inhibitory receptors, can be blocked by anti-KIR (lirimumab) and anti-NKG2A (monalizumab); however, there are no studies on the use of these drugs (lirimumab e monalizumab) in STS. Blocking these receptors restores the cytotoxic activity of the NK cells.