Differential quantities of immune checkpoint-expressing CD8 T cells in soft tissue sarcoma subtypes

Abstract

IntroductionLocal T-cell immunity is recognized for its contribution to the evolution and therapy response of various carcinomas. Here, we investigated characteristics of tumor-infiltrating lymphocytes (TILs), as well as T-cell evasive mechanisms in different soft tissue sarcoma (STS) subtypes.MethodsLiposarcoma, gastrointestinal stromal tumor (GIST), leiomyosarcoma, myxofibrosarcoma and pleomorphic sarcomas were assessed for T-cell numbers and phenotypes using flow cytometry. Next-generation sequencing was used to analyze T-cell receptor repertoire, mutational load, immune cell frequencies, and expression of immune-related genes.ResultsGIST, myxofibrosarcoma and pleomorphic sarcoma showed high numbers of CD8+ TILs, with GIST having the lowest fraction of effector memory T cells. These TILs coexpress the immune checkpoints PD1, TIM3, and LAG3 in myxofibrosarcoma and pleomorphic sarcoma, yet TILs coexpressing these checkpoints were near negligible in GIST. Fractions of dominant T-cell clones among STS subtypes were lowest in GIST and liposarcoma, whereas mutational load was relatively low in all STS subtypes. Furthermore, myeloid-derived cells and expression of the costimulatory ligands CD86, ICOS-L and 41BB-L were lowest in GIST when compared with other STS subtypes.ConclusionSTS subtypes differ with respect to number and phenotypical signs of antitumor responsiveness of CD8+ TILs. Notably, GIST, myxofibrosarcoma and pleomorphic sarcoma harbor high numbers of CD8+ T cells, yet in the GIST microenvironment, these T cells are less differentiated and non-exhausted, which is accompanied with a relatively low expression of costimulatory ligands.

Soft Tissue Sarcoma: An Insight on Biomarkers at Molecular, Metabolic and Cellular Level

“…In Ewing’s sarcoma and angiosarcoma, high levels of CD8 + cells are associated with increased survival [ 31 , 32 ]. A high number of CD8 + has also been detected in myxofibrosarcoma and pleomorphic sarcoma [ 33 ].…”

“…In a study on immune checkpoints linked to CD8 + TILs, an elevated presence of TIM3 + cells was observed in myxofibrosarcoma and pleomorphic sarcoma compared to liposarcoma. Co-expression with PD1 is frequent [ 33 ].…”

“…In a study carried out on 163 STS-affected patients, it was found that the frequency of CD8 + and CD4 + T lymphocytes expressing LAG3 is higher than in healthy controls; moreover, the expression is correlated with the presence of TILs CD8 + , with a severe prognosis and advanced tumor stage [ 45 ]. LAG3 is often co-expressed with PD1, and rarely with TIM3 [ 33 ].…”

Molecular Determinants of Soft Tissue Sarcoma Immunity: Targets for Immune Intervention

“…Transcriptomic sequencing (e.g., bulk and single-cell RNA sequencing, Nanostring technology) and proteomic-based approaches (e.g., MS-CyTOF) integrated the tumor genetic landscape with the tumor immune profiling. In this context, NGS techniques have been applied to sarcoma to derive immune cell frequencies, the expression profile of immune-related genes, and also the T cell repertoire at the tumor site [ 22 ]. Intriguingly, while for long time sarcomas have been considered neglected by the host immune system, these omics approaches contributed to picture different scenarios of immune complexity at the TME level, not only across different histologies, but also within a single histology, reflecting the distinctive genetic and epigenetic background of STSs.…”

Crosstalk between Macrophages and Myxoid Liposarcoma Cells Increases Spreading and Invasiveness of Tumor Cells

“…For instance, immunotherapy targeting the cancer-testis antigen (NY-ESO-1) which is aberrantly expressed in MLPS [42] and has been reported to elicit both humoral and specific CD8+ cytotoxic T-cell immune responses [43,44] could improve the survival of patients affected by high grade MLPS. Furthermore, it has to be taken into account that most studies lump together different sarcoma subtypes that might exhibit immunological differences [45] and were carried out on different tissue areas, including tissue microarrays that may poorly represent the heterogeneity of histological pictures, compared to larger tumor sections.…”