Influence of tumor-infiltrating immune cells on local control rate, distant metastasis, and survival in patients with soft tissue sarcoma

Abstract

Soft tissue sarcomas (STS) are considered non-immunogenic, although distinct entities respond to antitumor agents targeting the tumor microenvironment. This study's aims were to investigate relationships between tumor-infiltrating immune cells and patient/tumor-related factors, and assess their prognostic value for local recurrence (LR), distant metastasis (DM), and overall survival (OS). One-hundred-eighty-eight STS-patients (87 females [46.3%]; median age: 62.5 years) were retrospectively analyzed. Tissue microarrays (in total 1266 cores) were stained with multiplex immunohistochemistry and analyzed with multispectral imaging. Seven cell types were differentiated depending on marker profiles (CD3+, CD3+ CD4+ helper, CD3+ CD8+ cytotoxic, CD3+ CD4+ CD45RO+ helper memory, CD3 + CD8+ CD45RO+ cytotoxic memory T-cells; CD20 + B-cells; CD68+ macrophages). Correlations between phenotype abundance and variables were analyzed. Uni-and multivariate Fine&Gray and Cox-regression models were constructed to investigate prognostic variables. Model calibration was assessed with C-index. IHC-findings were validated with TCGA-SARC gene expression data of genes specific for macrophages, T-and B-cells. B-cell percentage was lower in patients older than 62.5 years (p = .013), whilst macrophage percentage was higher (p = .002). High B-cell (p = .035) and macrophage levels (p = .003) were associated with increased LR-risk in the univariate analysis. In the multivariate setting, high macrophage levels (p = .014) were associated with increased LR-risk, irrespective of margins, age, gender or B-cells. Other immune cells were not associated with outcome events. High macrophage levels were a poor prognostic factor for LR, irrespective of margins, B-cells, gender and age. Thus, anti-tumor, macrophage-targeting agents may be applied more frequently in tumors with enhanced macrophage infiltration.

The immune subtypes and landscape of sarcomas

“…The critical factor determining prognosis might be the dominance of the immune-suppressive environment or the stimulatory environment. Smolle et al [ 26 ] investigated relationships between tumor-infiltrating immune cells and patient/tumor-related factors in soft tissue sarcomas and assessed their prognostic value. They found that high macrophage levels were associated with increased local recurrence risk, irrespective of margins, age, sex or B-cell level.…”

“…Genetically, human sarcomas are classified based on the abnormalities that drive their pathogenesis, and sarcomas can be categorized into two main groups: (1) sarcomas with simple and specific chromosomal changes (often translocations) and a low mutational burden and (2) karyotypically complex sarcomas with numerous copy number aberrations and a moderate mutational burden [ 24 ]. Among these copy number-driven tumors, UPS, dedifferentiated liposarcoma (DDLPS) and—to a lesser extent—leiomyosarcoma (LMS) can exhibit durable responses to immune checkpoint inhibitors, possibly due to heterogeneity within the tumors [ 25 , 26 ]. However, translocation-associated subtypes, synovial sarcoma (SS), and MLPS tend to show mixed results [ 24 ].…”

The Immune Contexture of Liposarcoma and Its Clinical Implications

“…Compared to DDLPS, other karyotypically complex STS have a similar or lower proportion of immune-hot tumors. In contrast, studies that lack LPS subtype differentiation reported a relatively low rate of TILs in LPS compared to other STS subtypes [ 94 , 95 , 96 , 97 ]. As this observation strongly implies that the heterogeneity of LPS infiltration cannot be reflected by pooling various LPS subtypes, it should be taken into consideration for future study design.…”

“…While there are reports correlating high CD3 + , CD8 + , and CD4 + T cell infiltration with a significantly favorable outcome [ 100 , 101 ], others showed that high CD3 + and CD4 + infiltrates tend to predict a negative prognosis [ 102 ]. Furthermore, several studies did not find any association between T cell infiltration and patient outcome [ 95 , 96 ]. The prognostic value of high FoxP3 + Treg levels is also undefined in mixed STS cohorts (including LPS) since no impact on OS, but a negative impact on local recurrence in multivariate analysis was demonstrated [ 95 , 102 ].…”

“…In LPS as well as mixed STS cohorts (with or without LPS), T cells are generally more frequent than CD20 + B cells [ 88 , 96 , 117 ]. Nevertheless, Sorbye et al identified high levels of CD20 + B cells as an independent positive prognostic marker for DSS in STS (including LPS) with wide resection margins [ 100 ].…”