Tumor microenvironment of soft tissue sarcomas and it's predictive significance in modern oncological treatment

Soft tissue sarcomas (STSs) are malignant tumors of mesenchymal origin, characterized by an extreme heterogeneity in histological composition, biological behavior, and clinical manifestation. Most STSs are chemo- and radiotherapy resistant. A key prognostic factor predicting the risk of distant metastases and affecting the overall survival is the tumor grade. However, grade has not been associated with the risk of local recurrence. Radical surgical procedure is in many cases the only possible treatment modality or at least plays a main role in the multimodal treatment. For patients with distant metastases, the treatment options are very limited. The chemosensitivity of STSs is generally very low, with the exception of several less common subtypes, and accounts for only 5-10% of the cases. In many cases, radiotherapy is a standard part of the treatment protocol. It is usually given in either neoadjuvant or adjuvant settings. However, radiotherapy administration in generalized patients does not improve the prognosis. Cancer immunotherapy is a therapeutic modality that utilizes the physiological cytotoxic antitumoral abilities of the immune cells. Therefore, it does not target the rapidly proliferating tumor cells but rather stimulates the immune cells. A wide variety of different strategies have been...Sarkomy (Soft tissue sarcomas/STSs) jsou maligní nádory mezenchymálního původu, vyznačující se extrémní heterogenitou v histologické skladbě, biologickém chování i klinickém projevu. Většina se vyznačuje chemorezistencí a radiorezistencí. Klíčovým prognostickým faktorem pro celkové přežívání a riziko vzdálených metastáz je histopatologický stupeň diferenciace neboli grade nádoru. Grade ovšem nemá vliv na riziko lokální recidivy. Radikální chirurgický zákrok je často jedinou možnou léčebnou modalitou nebo minimálně hraje hlavní roli v terapii. U generalizovaného onemocnění jsou možnosti léčby značně omezené. Chemosenzitivita STSs je všeobecně velmi nízká, s výjimkou některých méně častých podtypů, a celkově činí jenom 5-10 %. Radioterapie je v mnoha případech standardní součástí léčebného protokolu. Podává se zpravidla v neoadjuvantním nebo adjuvantním podání, ovšem její využití u generalizovaných pacientů je okrajové a nezlepšuje prognózu. Protinádorová imunoterapie je terapeutická modalita, která využívá fyziologických schopností buněk imunitního systému v boji proti nádorovému onemocnění. Není tedy založena na cílené eliminaci rychle proliferujících nádorových buněk, nýbrž na stimulaci imunitních buněk za účelem likvidace nádorových antigenů. V oblasti imunoterapie měkkotkáňových sarkomů bylo...III. chirurgická klinika 1. LF UK a FN Motol3rd Department of Surgery First Faculty of Medicine Charles University and Motol University HospitalFirst Faculty of Medicine1. lékařská fakult

Tumor microenvironment of soft tissue sarcomas and it's predictive significance in modern oncological treatment

Soft tissue sarcomas (STSs) are malignant tumors of mesenchymal origin, characterized by an extreme heterogeneity in histological composition, biological behavior, and clinical manifestation. Most STSs are chemo- and radiotherapy resistant. A key prognostic factor predicting the risk of distant metastases and affecting the overall survival is the tumor grade. However, grade has not been associated with the risk of local recurrence. Radical surgical procedure is in many cases the only possible treatment modality or at least plays a main role in the multimodal treatment. For patients with distant metastases, the treatment options are very limited. The chemosensitivity of STSs is generally very low, with the exception of several less common subtypes, and accounts for only 5-10% of the cases. In many cases, radiotherapy is a standard part of the treatment protocol. It is usually given in either neoadjuvant or adjuvant settings. However, radiotherapy administration in generalized patients does not improve the prognosis. Cancer immunotherapy is a therapeutic modality that utilizes the physiological cytotoxic antitumoral abilities of the immune cells. Therefore, it does not target the rapidly proliferating tumor cells but rather stimulates the immune cells. A wide variety of different strategies have been..

Novel Insights into the Immunotherapy of Soft Tissue Sarcomas: Do We Need a Change of Perspective?

Soft tissue sarcomas (STSs) are rare mesenchymal tumors. With more than 80 histological subtypes of STSs, data regarding novel biomarkers of strong prognostic and therapeutic value are very limited. To date, the most important prognostic factor is the tumor grade, and approximately 50% of patients that are diagnosed with high-grade STSs die of metastatic disease within five years. Systemic chemotherapy represents the mainstay of metastatic STSs treatment for decades but induces response in only 15–35% of the patients, irrespective of the histological subtype. In the era of immunotherapy, deciphering the immune cell signatures within the STSs tumors may discriminate immunotherapy responders from non-responders and different immunotherapeutic approaches could be combined based on the predominant cell subpopulations infiltrating the STS tumors. Furthermore, understanding the immune diversity of the STS tumor microenvironment (TME) in different histological subtypes may provide a rationale for stratifying patients according to the TME immune parameters. In this review, we introduce the most important immune cell types infiltrating the STSs tumors and discuss different immunotherapies, as well as promising clinical trials, that would target these immune cells to enhance the antitumor immune responses and improve the prognosis of metastatic STSs patients

Patient with composite haemangioendothelioma containing angiosarcoma-like areas in the setting of congenital lymphoedema mimicking Stewart-Treves syndrome: a case report

Abstract Background Composite haemangioendothelioma is a rare vascular neoplasm with indolent to intermediate malignant potential. Diagnosis of this disease relays on histopathological identification of at least two different morphologically distinctive vascular components in proper clinical settings. Exceedingly rare cases of this neoplasm can exhibit areas resembling high-grade angiosarcoma, which does not change the biological behaviour. Such lesions tend to occur in the setting of chronic lymphoedema and thus, can mimic Stewart-Treves syndrome, which has a much worse clinical outcome and prognosis. Case presentation We present a case of 49 years old male suffering from chronic lymphoedema of the left lower extremity who had developed a composite haemangioendothelioma with high grade angiosarcoma-like areas mimicking the Stewart-Treves syndrome. Given the multifocality of the disease, the only potentially curable surgical treatment would be hemipelvectomy, which was refused by the patient. The patient has been followed-up, with no signs of local progression of the remaining disease, nor a distant spread outside the involved extremity for two years. Conclusions Composite haemangioendothelioma represents a rare malignant vascular tumour, with significantly more favourable biological behaviour than angiosarcoma, even in cases where angiosarcoma-like areas are present. For that reason, composite haemangioendothelioma can be easily misdiagnosed as true angiosarcoma. The rarity of this disease unfortunately hampers the development of clinical practice guidelines and the implementation of treatment recommendations. Most of the patients with localized tumour are treated by wide surgical resection, without neo- or adjuvant radiotherapy or chemotherapy. However, in the case of this diagnosis, the watch-and-wait approach is better than mutilating procedure, highlighting the necessity of establishing of the correct diagnosis

Oncostatin M and Nivolumab Affect the Cytotoxic T-Cell Proportions and the Susceptibility to TRAIL-Induced Death in Non-Leukocyte Cell Subpopulations in Soft Tissue Sarcomas

Introduction: Soft tissue sarcomas (STSs) are malignant tumors arising from mesenchymal tissues. Patients with advanced and metastatic STSs have low overall survival rates and relatively limited treatment options. Oncostatin M (OSM) is a pleiotropic cytokine that was shown to carry both pro- and anti-tumorigenic properties in various cancer types. However, the role of OSM in STSs has not yet been elucidated. Moreover, the potential additive effects of combining OSM and anti-PD-1 therapy have not been carried out so far. Methods: The aim of this study was to determine the effects of in vitro OSM administration on liposarcoma, leiomyosarcoma, and myxofibrosarcoma immune cells isolated from peripheral blood and tumor tissues and the potential cooperative nature of OSM and nivolumab in treating these STSs. We designed a cohort study to explore novel histology-driven therapies in our target STSs. The immune cells were isolated from the peripheral blood and tumors of patients with STS, and the proportions and phenotypes of immune cells were evaluated with flow cytometry after cultivation with therapeutic monoclonal antibodies. Results: The proportion of peripheral CD45(+) cells was not affected by OSM but was significantly increased by nivolumab, whereas both treatments had an effect on CD8(+) T cells. In tumor tissues, CD8(+) T cell and CD45(-) TRAIL(+) cell cultures were boosted by nivolumab and significantly enriched by OSM. Our data suggest that OSM may play a role in the treatment of leiomyosarcoma, myxofibrosarcoma, and liposarcoma. Conclusion: In conclusion, the biological efficacy of OSM is reflected in the tumor microenvironment rather than in the peripheral blood of the patients in our cohort, and nivolumab could potentiate its mechanism of action in selected cases. Nevertheless, more histotype-tailored studies are needed to fully understand the functions of OSM in STSs

A novel anti-CD47-targeted blockade promotes immune activation in human soft tissue sarcoma but does not potentiate anti-PD-1 blockade

Purpose: The treatment options for metastatic soft tissue sarcomas (STSs) are limited. In most cases, immunotherapy with immune checkpoint inhibitors has not been successful so far. Macrophages dominate the immune landscape of STSs; thus, combinatorial strategies aiming at both tumor-infiltrating lymphocytes and macrophages may represent a particularly relevant treatment approach for metastatic or recurrent STSs. Methods: In this cohort study, 66 patients who underwent surgery for STSs were enrolled. Tumor cells and tumor-infiltrating immune cells were analyzed using flow cytometry and immunohistochemistry. In cell suspensions obtained from surgical resections, human T cells were activated by superparamagnetic polymer beads and cultured at a concentration of 0.3 × 106/µl in the absence or presence of therapeutic monoclonal antibodies (anti-PD-1, anti-CD47, and anti-PD-1 + anti-CD47). Supernatants from cell suspensions were analyzed using multiplex Luminex cytokine bead-based immunoassays. Results: The most profound response to anti-CD47 therapy was observed in an undifferentiated pleiomorphic sarcoma which also displayed high expression of CD47 in the tumor microenvironment. Both anti-PD-1 and anti-CD47 therapies drastically increased the production of pro-inflammatory cytokines in the tumor microenvironment of STSs, but co-administration of both agents did not further increase cytokine secretion. Furthermore, all patient samples treated with a combination of both anti-PD-1 and anti-CD47 antibodies showed a dramatic reduction in cytokine secretion. Conclusion: Our findings suggest that anti-PD-1 and anti-CD47 therapies do not enhance each other, and the combined application of anti-PD-1 and anti-CD47 agents in vitro limits rather than potentiates their efficacy

The Immune Contexture of Liposarcoma and Its Clinical Implications

Simple Summary Liposarcomas (LPS) are malignancies arising from adipose tissue. Based on the histological appearance, five subtypes are distinguished: well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. Immune cells can infiltrate the tumor microenvironment (TME) of LPS and can either promote an efficient antitumor immune response or mediate immunosuppression paving the way for immune evasion of the tumor. The LPS subtypes display different TME characteristics and vary in regard to immune cell infiltration, ranging from the generally lowly infiltrated MLPS to the highly infiltrated DDLPS where immunological determinants predict response to novel antibody-based immunotherapy. Thus, immune cells in the TME can significantly affect response to therapy, disease progression, and patient survival. This review aims to decipher the immune contexture of LPS as well as its clinical association and highlights differences between the LPS subtypes that may have implications for the design of novel treatment strategies. Liposarcomas (LPS) are the most frequent malignancies in the soft tissue sarcoma family and consist of five distinctive histological subtypes, termed well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. They display variations in genetic alterations, clinical behavior, and prognostic course. While accumulating evidence implicates a crucial role of the tumor immune contexture in shaping the response to anticancer treatments, the immunological landscape of LPS is highly variable across different subtypes. Thus, DDLPS is characterized by a higher abundance of infiltrating T cells, yet the opposite was reported for MLPS. Interestingly, a recent study indicated that the frequency of pre-existing T cells in soft tissue sarcomas has a predictive value for immune checkpoint inhibitor (CPI) therapy. Additionally, B cells and tertiary lymphoid structures were identified as potential biomarkers for the clinical outcome of LPS patients and response to CPI therapy. Furthermore, it was demonstrated that macrophages, predominantly of M2 polarization, are frequently associated with poor prognosis. An improved understanding of the complex LPS immune contexture enables the design and refinement of novel immunotherapeutic approaches. Here, we summarize recent studies focusing on the clinicopathological, genetic, and immunological determinants of LPS