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

Abstract

Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic strategies urgently needed. From a molecular point of view, STSs can be classified as translocation-related and those with a heavily rearranged genotype. Although only the latter display an increased mutational burden, molecular profiles suggestive of an “immune hot” tumor microenvironment are observed across STS histologies, and response to immunotherapy has been reported in both translocation-related and genetic complex STSs. These data reinforce the notion that immunity in STSs is multifaceted and influenced by both genetic and epigenetic determinants. Cumulative evidence indicates that a fine characterization of STSs at different levels is required to identify biomarkers predictive of immunotherapy response and to discover targetable pathways to switch on the immune sensitivity of “immune cold” tumors. In this review, we will summarize recent findings on the interplay between genetic landscape, molecular profiling and immunity in STSs. Immunological and molecular features will be discussed for their prognostic value in selected STS histologies. Finally, the local and systemic immunomodulatory effects of the targeted drugs imatinib and sunitinib will be discussed.

Deciphering the Genomic Landscape and Pharmacological Profile of Uncommon Entities of Adult Rhabdomyosarcomas

“…In particular, no alterations were detected in the expression of ALK, MTOR, KIT, PDGFRA, NTRK1, NTRK2, and NTRK3, which are the targets of crizotinib, everolimus, imatinib, and larotrectenib, respectively. These results are suggestive of the refractoriness of these diseases to several treatments currently used for the management of other STS histotypes (e.g., anthracyclines, trabectedin or immunotherapy [ 39 , 40 ]) and support the clinical observation of the limited availability of therapeutic options and poor outcome of adult RMS patients. The observed results prompted us to deepen the investigation of molecular features of RMS1 lesion through a larger RNA-seq panel.…”

Novel Hypoxia-Associated Gene Signature Depicts Tumor Immune Microenvironment and Predicts Prognosis of Colon Cancer Patients

“…Although most targeted drugs were not approved to be used as the first-line therapy for CRC by FDA, some studies revealed that tyrosine kinase inhibitor (TKI), including bosutinib, imatinib, and sunitinib, could enhance the infiltration of cytotoxic and effector T cells, which would directly affect the efficacy of immunotherapy ( Roulleaux Dugage et al, 2021 ; Tazzari et al, 2021 ; Hirata et al, 2022 ). These studies revealed that the application of TKI might be positively related to the infiltration of pro-inflammation immune cells, which meant that the combination therapy of TKI and ICB might receive better efficacy than monotherapy.…”

Correlative Study on the Relationship between the Expression of m6a-Related Genes and the Prognosis and Immunotherapy of Soft Tissue Sarcoma

“…For example, patients with mutations in the RB1 tumor suppressor gene have a significantly increased incidence of STS [39]. Furthermore, structural activation of oncogenic signaling pathways caused by oncogene mutations negatively affects the TME by promoting intratumoral immune cell rejection or facilitating the recruitment of immunosuppressive cells [40]. However, the treatment of STS still lacks efficient methods.…”