Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

SIMPLE SUMMARY: Treatment modalities for sarcoma have not changed significantly for the past few years despite 25–50% of patients experiencing relapse or progressing to metastatic diseases that become resistant to standard of care therapy, indicating an unmet need for better treatment strategies. While immunotherapy has shown promising results in other types of cancer such as melanoma, first generation immunotherapy trials in sarcomas patients showed unsatisfactory results. Nevertheless, the progressive deepening of our knowledge about the immune landscape of sarcomas and the consequent ability to dissect the heterogeneity of these tumours are leading to a more accurate stratification of patients to be treated with immunotherapy. In addition, new targets are being exploited by a variety of promising immunotherapeutic treatments, which are expected to considerably improve the clinical management of sarcoma patients. ABSTRACT: Sarcomas are a rare type of a heterogeneous group of tumours arising from mesenchymal cells that form connective tissues. Surgery is the most common treatment for these tumours, but additional neoadjuvant or adjuvant chemotherapy or radiation therapies may be necessary. Unfortunately, a significant proportion of patients treated with conventional therapies will develop metastatic disease that is resistant to therapies. Currently, there is an urgent need to develop more effective and durable therapies for the treatment of sarcomas. In recent years immunotherapies have revolutionised the treatment of a variety of cancers by restoring patient anti-tumour immune responses or through the adoptive infusion of immune effectors able to kill and eliminate malignant cells. The clinicopathologic and genetic heterogeneity of sarcomas, together with the generally low burden of somatic mutations potentially generating neoantigens, are currently limited to broad application of immunotherapy for patients with sarcomas. Nevertheless, a better understanding of the microenvironmental factors hampering the efficacy of immunotherapy and the identification of new and suitable therapeutic targets may help to overcome current limitations. Moreover, the recent advances in the development of immunotherapies based on the direct exploitation or targeting of T cells and/or NK cells may offer new opportunities to improve the treatment of sarcomas, particularly those showing recurrence or resistance to standard of care treatments.