The Role of Immunotherapy in the Management of Soft Tissue Sarcomas: Current Landscape and Future Outlook

Abstract

Soft tissue sarcomas (STS) are a subset of sarcoma, a rare group of heterogeneous malignancies of mesenchymal origin. Current standard of care involves surgical resection with systemic chemotherapy used to treat high-risk localized and metastatic disease. Though classically thought to be immunologically quiet tumors, STS interact with the immune system, undergoing immunoediting that alters tumor immunogenicity and the tumor microenvironment. Recent advances with immune checkpoint inhibition have led to clinical trials exploring the efficacy of immunotherapy in treating STS. Results from these trials point to histologic subtype–specific clinical activity of immune checkpoint blockade. In addition, combinatorial strategies adding immune checkpoint inhibition to local or systemic therapies for STS have further increased their efficacy. Targeted immunotherapies using engineered T-cell receptor–based approaches also show increasing promise as treatment options for some patients with STS. Adoptive transfer of autologous T cells targeting NY-ESO-1 and MAGE-A4 have high response rates in sarcomas expressing these antigens, although recurrence is often seen in responding patients. Future work must focus on identifying primary and acquired mechanisms of resistance to these therapies, and extend T-cell receptor discovery to other tumor-associated antigens.

The immune subtypes and landscape of sarcomas

“…It is thus critical to investigate novel therapeutic targets to apply new treatments with improved clinical efficacy. Immunomodulation in different forms, such as checkpoint blockers, tumor vaccines, and CAR-T cells, has become an area of interest for many tumors, and sarcoma is no exception [ 23 ]. However, sarcomas are thought to be “cold” tumors that show initial resistance to ICIs due to the lack or paucity of tumor T-cell infiltration [ 23 ].…”

“…Immunomodulation in different forms, such as checkpoint blockers, tumor vaccines, and CAR-T cells, has become an area of interest for many tumors, and sarcoma is no exception [ 23 ]. However, sarcomas are thought to be “cold” tumors that show initial resistance to ICIs due to the lack or paucity of tumor T-cell infiltration [ 23 ]. Furthermore, sarcomas tend to show frequent overexpression of major suppressive cytokines such as vascular endothelial growth factor (VEGF) [ 33 ] or TGF-β1 [ 34 ], constituting hostile TME resistance to immune therapies.…”

“…For example, destruction of tumor cells by local injection of oncolytic viruses promotes release of tumor-associated antigens (TAAs) that prime the immune system, thereby promoting a more effective systemic antitumor immune response in locally advanced or metastatic sarcoma [ 22 ]. Several recent clinical studies have provided solid evidence that the ORR can be improved by enhancing antitumor immunity with combination approaches such as ICIs together with radiotherapy or systemic therapy [ 23 ]. Given the TME of sarcoma, most histological subtypes may require a multipronged approach to manipulate the microenvironment and thus induce effective antitumor immunity.…”

The potential and promise for clinical application of adoptive T cell therapy in cancer

“…The effectiveness of transferring autologous NY-ESO-1-specific T cells was assessed in HLA-A*02 patients with synovial sarcoma (SS). This marked the first clinical study of designed TCR treatment for sarcoma, validating tumoral NY-ESO-1 expression [ 65 ]. Another group of SS patients with advanced HLA-A*02, separated into 4 groups based on tumoral NY-ESO-1 expression, were treated with the NY-ESO-1-targeting specific peptide enhanced affinity receptor (SPEAR) T cells in a pilot trial (NCT01343043).…”

Immune checkpoint inhibitor response in sarcomas associates with immune infiltrates and increased expression of transposable elements and viral response pathways

“…Immune checkpoint inhibition (ICI) has been studied in sarcomas, and activity has been noted with nivolumab (anti-PD-1) alone or in combination with ipilimumab (anti-CTLA-4) 7 or with pembrolizumab (anti-PD-1) as a single agent 8 . Efforts to enhance the activity of ICI through combination with other immune-modulatory drugs or with cytotoxic therapies has revealed variable response rates, which likely depend on the drug combination and sarcoma subtype (recently reviewed 9 ). In parallel, predictive biomarkers for ICI response in sarcoma are being explored.…”