Targeted therapies and checkpoint inhibitors in sarcoma

Abstract

Sarcomas are defined as a group of mesenchymal malignancies with over 100 heterogeneous subtypes. As a rare and difficult to diagnose entity, micrometastasis is already present at the time of diagnosis in many cases. Current treatment practice of sarcomas consists mainly of surgery, (neo)adjuvant chemo- and/or radiotherapy. Although the past decade has shown that particular genetic abnormalities can promote the development of sarcomas, such as translocations, gain-of-function mutations, amplifications or tumor suppressor gene losses, these insights have not led to established alternative treatment strategies so far. Novel therapeutic concepts with immunotherapy at its forefront have experienced some remarkable success in different solid tumors while their impact in sarcoma remains limited. In this review, the most common immunotherapy strategies in sarcomas, such as immune checkpoint inhibitors, targeted therapy and cytokine therapy are concisely discussed. The programmed cell death (PD)-1/PD-1L axis and apoptosis-inducing cytokines, such as TNF-related apoptosis-inducing ligand (TRAIL), have not yielded the same success like in other solid tumors. However, in certain sarcoma subtypes, e.g. liposarcoma or undifferentiated pleomorphic sarcoma, encouraging results in some cases when employing immune checkpoint inhibitors in combination with other treatment options were found. Moreover, newer strategies such as the targeted therapy against the ancient cytokine macrophage migration inhibitory factor (MIF) may represent an interesting approach worth investigation in the future.

Tertiary lymphoid structures in cancer: immune mechanisms and clinical implications

“…Of note, the expression levels of immune checkpoint proteins and tumor antigens within TLS determine the immune response in TLS. Common checkpoint proteins include PD‐1, CTL‐associated antigen‐4 (CTLA‐4), T cell immunoglobulin (TIM), lymphocyte‐activation gene 3 (LAG‐3) 70 . PD‐1 affects the activity of effector T cells, 71 while CTLA‐4 affects the initial activation.…”

“…Common checkpoint proteins include PD‐1, CTL‐associated antigen‐4 (CTLA‐4), T cell immunoglobulin (TIM), lymphocyte‐activation gene 3 (LAG‐3). 70 PD‐1 affects the activity of effector T cells, 71 while CTLA‐4 affects the initial activation. Though CTLA‐4 is principally expressed on CD8+ T cells, its blockade mainly interferes with 2 T cell subsets: extends the T helper cell‐dependent immune responses, and downregulates the immune‐suppressive effects of Tregs.…”

Correlation analysis of disulfidptosis-related gene signatures with clinical prognosis and immunotherapy response in sarcoma

“…With over 100 distinct subtypes, these tumors can manifest in multiple anatomical sites. Due to its rarity and diagnostic challenges, metastasis often transpires during the underdiagnosed disease stage 1 . However, the survival rate for localized sarcoma can become 70–75% by employing a comprehensive approach associated with systemic therapy, chemotherapy, and effective management of the primary tumor via surgery and/or radiation 2 .…”

Predicting prognosis and immune status in sarcomas by identifying necroptosis-related lncRNAs

“…Due to the tumor compensatory AGING mechanism, tumor heterogeneity and complex tumor microenvironment (TME), targeted therapy for sarcomas is limited to partial tumor subtypes [5]. As tumor research has progressed, TME has shown a notable impact on the progression of sarcomas, and immunotherapy has become a novel therapeutic choice for sarcomas [6,7]. Therefore, it is particularly important to identify new biomarkers and understand their importance in TME for finding new potential therapeutic strategies of sarcomas and improving the prognosis of sarcoma patients [8].…”