Immune Status in Soft Tissue Sarcoma: Implications for Immunotherapy
Soft Tissue Sarcomas are a rare and heterogeneous group of tumors, which have a characteristic complexity, leading to a difficult diagnosis and a lack of response to treatment. Based on a nice review, we introduce here the role of immune cells, soluble plasmatic factors, immune checkpoints; and the expression of immune-related genes predicting survival, response to therapy, and potential immunotherapeutic agents or targets in Soft Tissue Sarcomas.
Immunotherapy in STS
Rapidly growing tumours contain large numbers of leucocytes. These cells play a part in both defence and repair; however, reparative functions can also support tumour growth. Intratumoural infections may reactivate defensive functions, causing tumour regression. Spontaneous tumour regression has followed bacterial, fungal, viral, and protozoal infections. This phenomenon inspired the development of numerous rudimentary cancer immunotherapies, but the idea dates back more than 100 years, to a young surgeon who was willing to think outside the box. Coley took advantage of this natural phenomenon, developing a killed bacterial vaccine for cancer in the late 1800s. In 1891, William B. Coley injected streptococcal organisms into a patient with inoperable sarcoma cancer. He thought that the infection he produced would have the side effect of shrinking the malignant tumor. He was successful, and this was one of the first examples of immunotherapy. Over the next forty years, as head of the Bone Tumor Service at Memorial Hospital in New York, Coley injected more than 1000 cancer patients with bacteria or bacterial products. These products became known as Coley's Toxins. He and other doctors who used them reported excellent results, especially in bone and soft-tissue sarcomas.
Despite his reported good results, Coley's Toxins came under a great deal of criticism because many doctors did not believe his results. This criticism, along with the development of radiation therapy and chemotherapy, caused Coley's Toxins to gradually disappear from use. However, the modern science of immunology has shown that Coley's principles were correct and that some cancers are sensitive to an enhanced immune system. Because research is very active in this field, William B. Coley, a bone sarcoma surgeon, deserves the title "Father of Immunotherapy." (Hoption Cann, van Netten et al. 2003)
It is now clear that the immune microenvironment is highly variable in STS, and this variability is frequently justified by STS heterogenicity. Despite this heterogenicity, clinical trials continue to incorporate various sarcoma subtypes to obtain the minimum number of patients required. Although there have been hints of positive responses to immunotherapy trials for STS, most trials have been negative or are not representative of all STS subtypes (Sousa, Almeida et al. 2021).
As was mentioned before, the expression of PD-1 and PD-L1 were present in some studies and absent in others, which appears to depend on the STS subtype. The presence of these immune checkpoints in some subtypes offers a promise for immunotherapy based on checkpoint inhibitors in these specific subtypes. Unfortunately, clinical trials testing immune checkpoint inhibitors in STS have not showed the impressive results achieved for many other cancers. The intention of the first study was to analyze the efficacy of targeting the immune checkpoint CTLA-4 with ipilimumab in synovial sarcoma, but neither a clinical benefit nor immunological activity was demonstrated (Maki, Jungbluth et al. 2013). Similarly, uterine leiomyosarcoma patients did not respond to anti-PD-1 antibody nivolumab in a phase II study (Ben-Ami, Barysauskas et al. 2017). Later, the clinical trial SARC028 tested the anti-PD-1 therapy with pembrolizumab. Promising responses for specific subtypes were observed in this trial, such as dedifferentiated liposarcoma (DDLPS), undifferentiated pleomorphic sarcoma (UPS) (Tawbi, Burgess et al. 2017). To further investigate the effectiveness of pembrolizumab treatment in patients with STS, the SARC028 study enrolled an expansion cohort to include additional patients; 40 with UPS and 40 with LPS. The UPS cohort reached its primary endpoint, with an objective response rate in 9/40 patients (two complete and seven partial responses). The LPS group had an objective response rate in 4/39 patients (four partial responses) (Burgess, Bolejack et al. 2019). Moreover, the response to pembrolizumab was correlated to higher tumor-infiltrating lymphocytes at the baseline (Italiano, Bessede et al. 2022). Based on these promising results for specific subtypes of STS and in specific immune microenvironments, further research and correlative studies are required to improve the selection of patients for future clinical trials with immune checkpoint blockade in STS.
Besides immune checkpoint blockade, some other immunotherapies such as adoptive cell transfer, cancer vaccines and oncolytic viruses show promise for the future of sarcoma therapy. However, therapies that have gained traction for the treatment of other cancer types encounter challenges in sarcoma due to: (1) a lack of well established antigens in subtypes that can be targeted by vaccines, therapeutic antibodies or chimeric antigen receptors (CAR) therapy, (2) presence of extensive tumor heterogeneity and (3) a lack of characterization of the tumor microenvironment (TME) in unique subtypes. Therefore, it is necessary to select the patients who will benefit from this type of therapy carefully. The heterogenicity of STS implies that a “one size fits all” approach may be less successful. Furthermore, comprehensive immune profiling in combination with the evaluation of clinical features will be important to predict the response to therapy and survival. The immune profiling of each patient might lead to personalized therapy. Lastly, The dual role of immunity in cancer leads us to believe that combination approaches that both stimulate protective host responses and inhibit immune subversion tactics might be more efficacious. We will introduce the combination therapy of immune checkpoint co-stimulators or inhibitors with VEGF TKI inhibitor for STS in the next coming article. Stay tuned.
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