Tumor and Peripheral Immune Status in Soft Tissue Sarcoma: Implications for Immunotherapy

Abstract

Soft Tissue Sarcomas (STS) are a heterogeneous and rare group of tumors. Immune cells, soluble factors, and immune checkpoints are key elements of the complex tumor microenvironment. Monitoring these elements could be used to predict the outcome of the disease, the response to therapy, and lead to the development of new immunotherapeutic approaches. Tumor-infiltrating B cells, Natural Killer (NK) cells, tumor-associated neutrophils (TANs), and dendritic cells (DCs) were associated with a better outcome. On the contrary, tumor-associated macrophages (TAMs) were correlated with a poor outcome. The evaluation of peripheral blood immunological status in STS could also be important and is still underexplored. The increased lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR), higher levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and Tim-3 positive CD8 T cells appear to be negative prognostic markers. Meanwhile, NKG2D-positive CD8 T cells were correlated with a better outcome. Some soluble factors, such as cytokines, chemokines, growth factors, and immune checkpoints were associated with the prognosis. Similarly, the expression of immune-related genes in STS was also reviewed. Despite these efforts, only very little is known, and much research is still needed to clarify the role of the immune system in STS.

Keywords: cytokines; gene expression; immune checkpoints; immune monitoring; immunophenotyping; soft tissue sarcoma.

Figure 1

Expression levels of immune cell subtypes, cytokines, chemokines, growth factors, and soluble receptors and their prognostic value in STS. The TME has been associated with the prognosis in several tumors. However, in STS, this association is still underexplored. Immune cells such as B cell, DC, TANs, and NK have been associated with a positive prognosis (green). On the contrary, TAMs, and some soluble factors: LIF, IL-8, HGF, IL-2R, VEGF, MCP-3, TNF-R, IL-6, and M-CSF, have been associated with a negative prognosis (red). The prognostic value of MDSCs, Tregs, CD4 T cells, and CD8 T cells is not clear yet (gray) [11,22,24,26,40,42,44,45,46,47].

Figure 2

Prognostic value of immune checkpoints in STS. Several studies have been trying to correlate the presence of immune checkpoints with the prognosis of patients with STS. These studies have showed a negative prognostic value for B7-H3, PD-1, PD-L1, NKp30, B7-H6, Sirpα, CD47, CD155, LAG3, and IDO (red). A positive prognostic value was associated with the immune checkpoint E-Cadherin (green) [15,26,39,76,77,78,79,89,90,91,92].

Figure 3

STS studies correlating the expression levels of immune-related genes and their prognostic significance. In STS, the expression of immune-related genes remains underexplored, and consequently, the prognostic value of these genes is still unclear. However, five main studies aimed at understanding this correlation, and their results are represented in this figure. Immune-related genes correlated with a good prognosis in STS are represented in green. On the other hand, immune-related genes associated with a bad prognosis are represented in red. From the peripheral to the center, circles represent genes encoding extracellular proteins, genes encoding transmembrane proteins, genes encoding intracellular proteins, the method used, and the respective study’s first author and publication year [99,100,101,102,103]. ¹ Prognostic value in synovial sarcomas; ² Prognostic value in gastrointestinal stromal tumors; ³ Prognostic value in myxoid liposarcomas; ⁴ Prognostic value in sarcomas with complex genetics.