The Immune Contexture of Liposarcoma and Its Clinical Implications

Abstract

Liposarcomas (LPS) are the most frequent malignancies in the soft tissue sarcoma family and consist of five distinctive histological subtypes, termed well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. They display variations in genetic alterations, clinical behavior, and prognostic course. While accumulating evidence implicates a crucial role of the tumor immune contexture in shaping the response to anticancer treatments, the immunological landscape of LPS is highly variable across different subtypes. Thus, DDLPS is characterized by a higher abundance of infiltrating T cells, yet the opposite was reported for MLPS. Interestingly, a recent study indicated that the frequency of pre-existing T cells in soft tissue sarcomas has a predictive value for immune checkpoint inhibitor (CPI) therapy. Additionally, B cells and tertiary lymphoid structures were identified as potential biomarkers for the clinical outcome of LPS patients and response to CPI therapy. Furthermore, it was demonstrated that macrophages, predominantly of M2 polarization, are frequently associated with poor prognosis. An improved understanding of the complex LPS immune contexture enables the design and refinement of novel immunotherapeutic approaches. Here, we summarize recent studies focusing on the clinicopathological, genetic, and immunological determinants of LPS.

Keywords: immune architecture; immunotherapy; liposarcoma.

Figure 1

Characteristics of diverse liposarcoma (LPS) subtypes. Five distinct histological subtypes of LPS, including well-differentiated LPS (WDLPS), dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS (PLPS), and myxoid pleomorphic LPS (MPLPS) differ in clinicopathologic features, such as biologic behavior and patterns of disease progression. Genetic alterations in each subtype also display wide variations (Created with Biorender, Agreement No. JR24ANFF0H).

Figure 2

The histological LPS subtypes display different features of their immune contexture. Research mainly focuses on DDLPS and MLPS, whereas insights on the immune microenvironment of WDLPS and PLPS are scarce and lacking in the case of MPLPS. DDLPS is characterized by a higher infiltration of T cells and tumor-associated macrophages (TAMs) compared to MLPS and TAMs are outnumbering T cells in DDLPS while this was not observed in MLPS. Both subtypes exhibit low T cell receptor (TCR) clonality and additionally, MLPS tumors display low levels of human leukocyte antigen (HLA) class I expression. Response to pembrolizumab in DDLPS patients was correlated to a higher density of T cells and a higher proportion of PD-L1⁺ TAMs at baseline. Furthermore, the presence of tertiary lymphoid structures (TLS) in DDLPS is associated with response to pembrolizumab treatment and correlates with elevated infiltration levels of CD3⁺ and CD8⁺ T cells as well as CD20⁺ B cells. In MLPS, tumor cells can promote M2 polarization of TAMs which in turn can enhance the motility and invasiveness of MLPS cells. While several immune cell types are of undefined prognostic value in LPS, accumulating evidence suggests a link to positive prognosis for B cells and TLS in DDLPS and an association with negative prognosis for TAMs, both CD68⁺ and CD163⁺, in MLPS.