PRAME and HLA Class I expression patterns make synovial sarcoma a suitable target for PRAME specific T-cell receptor gene therapy

Abstract

Synovial sarcoma expresses multiple cancer testis antigens that could potentially be targeted by T-cell receptor (TCR) gene therapy. In this study we investigated whether PRAME-TCR-gene therapy could be an effective treatment for synovial sarcoma by investigating the potential of PRAME-specific T-cells to recognize sarcoma cells and by evaluating the expression patterns of PRAME and HLA class I (HLA-I) in synovial sarcoma tumor samples. All PRAME expressing sarcoma cell lines, including 2 primary synovial sarcoma cell cultures (passage < 3), were efficiently recognized by PRAME-specific T-cells. mRNA FISH demonstrated that PRAME was expressed in all synovial sarcoma samples, mostly in an homogeneous pattern. Immunohistochemistry demonstrated low HLA-I baseline expression in synovial sarcoma, but its expression was elevated in specific areas of the tumors, especially in biphasic components of biphasic synovial sarcoma. In 5/11 biphasic synovial sarcoma patients and in 1/17 monophasic synovial sarcoma patients, elevated HLA-I on tumor cells was correlated with infiltration of T-cells in these specific areas. In conclusion, low-baseline expression of HLA-I in synovial sarcoma is elevated in biphasic areas and in areas with densely infiltrating T-cells, which, in combination with homogeneous and high PRAME expression, makes synovial sarcoma potentially a suitable candidate for PRAME-specific TCR-gene therapy.

Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma

“…One such cancer type is synovial sarcoma (SyS) (3), a highly aggressive mesenchymal neoplasm that accounts for 10-20% of all soft-tissue sarcomas in young adults (4). SyS tumors homogenously express several immunogenic cancer-testis antigens (CTAs) (5)(6)(7)(8), which are recognized by circulating T cells in the peripheral blood of SyS patients (5)(6)(7). Nonetheless, T cell infiltration remains exceptionally low in these tumors, suggestive of yet unidentified immune evasion mechanisms.…”

Targeting cancer testis antigens in synovial sarcoma

“… 51 84 86 87 Biphasic SS has higher HLA I expression in the epithelioid components compared with monophasic SS; 5 out of 10 patients had focal high expression in biphasic tumors compared with 1 out of 16 patients with monophasic SS. 51 The overall deficiency of HLA I in SS has led to the idea that this might be a main mechanism by which SS is able to evade the immune system from either its own in vivo stimulation or via ex vivo therapeutics. 84 87 Giving IFNγ in patients with SS has been shown to increase the levels of HLA I expression in the tumor cells along with increasing the density of TIL.…”

Visual cohort comparison for spatial single-cell omics-data

“…During the immune response, T-cells infiltrate the sarcomas. Previous work has shown that synovial sarcomas can have areas with abundant T-cell infiltration (hot areas) and areas with very little T-cell infiltration (cold areas), in the same tumor [32]. The goal of this case study was to explore differences in the immune cell composition between these two types of areas.…”