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Cancer News: Soft tissue and bone sarcomas, a rare and malignant group of tumors, pose significant challenges in treatment due to their heterogeneity. Developing effective therapeutic strategies demands a deep understanding of the complex interactions within the tumor microenvironment (TME). One emerging avenue of research that is covered in this
Cancer News report, centers around tumor-associated macrophages (TAMs), which play a pivotal role in immunosuppression during tumor growth. The Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, and the Mossakowski Medical Research Centre, Polish Academy of Sciences, are at the forefront of investigating TAMs in the context of sarcomas.
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Tumor-associated macrophages (TAMs) and their impact on the microenvironment of sarcomas. TAMs display a pro-tumor phenotype with polarization toward M2-type macrophages. TAMs lead to modulation of tumor microenvironment (TME) by CD80/CTLA-4 and PD-1/PD-L1 interaction, secretion of MMP-9, COX2, IDO1, and several cytokines and chemokines e.g., IL-10, Il-34, IL-6, TGF-B, CSF1, VEGF. All of these factors lead to immunosuppression by activating regulatory T cells (TREG) and inactivating effector T cells. On the other hand, by activating the JAK/MAPK, JAK/STAT3, and JAK/PI3K/AKT signaling pathways, TAMs cause activation of NF-κB transcription factor and, as a result, tumor progression and promotion. Sarcoma cells, through the secretion of cytokines and the CSF1R interaction, lead to the recruitment of TAMs. Furthermore, through CD47/SIRPA signaling, tumor cells inhibit the function of phagocytosis in TAMs.
Understanding Sarcomas
Sarcomas encompass a diverse range of malignant mesenchymal tumors, comprising both soft tissue and bone sarcomas. The intricacies of treating these tumors lie in their various subtypes, each demanding a specific therapeutic approach. Amid the ongoing efforts to identify novel treatments, the focus on TAMs has emerged as a promising avenue.
TAMs in Sarcoma Microenvironment
TAMs are a subset of macrophages specifically recruited to the tumor microenvironment. These immune cells defy categorization into classical (M1) or alternative (M2) activation states, possessing characteristics of both groups. Their influence on the TME is profound, contributing to immunosuppression, tumor growth, and metastasis in sarcomas. High TAM levels are consistently associated with poor prognoses across various cancers, including sarcomas.
Polarization of TAMs and Signaling Pathways
The journey of macrophages transforming into TAMs is orchestrated by cytokines like IL-34, CSF1, and various VEGFs and chemokines, including CCL5 and CCL2. Factors such as inflammation, local hypoxia, and lactic acid levels trigger the differentiation of monocytes into TAMs. These TAMs often exhibit a pro-tumor M2-like phenotype, promoting tumor invasion, progression, and
metastasis.
The intricate signaling pathways involved in TAM function include p-STAT3/p-Erk1/2, PI3K/Akt, JAK/MAPK, and JAK/STAT3. TAMs express both M1 and M2 markers, making them versatile responders to different stimuli. Th1 and Th2 T cells further modulate TAMs into distinct functional subgroups, highlighting their adaptability within the dynamic TME.
Impact of TAMs on Sarcoma Clinical Outcomes
Numerous subtypes of sarcomas, including chondrosarcoma, osteosarcoma, liposarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma, exhibit a strong correlation between high TAM levels and poor overall survival rates. TAMs actively contribute to the immunosuppressive milieu, hindering the recognition and elimination of tumor cells by cytotoxic CD8+ T cells. The intricate network of suppressive markers, such as PD-1, PD-L1, CD80, SIRPA, CD206, CD209, CD146, CD14, CD68, CD163, and CSF1R, form a complex landscape influencing the clinical outcomes of sarcoma patients.
TAMs Function in Tumor Development
TAMs exert their influence on both the TME and tumor cells through the secretion of various cytokines, chemokines, and enzymes. This includes TGF-β, prostaglandins, IL-10, CCL22, CCL17, galectin-3 (Gal-3), and metalloproteinases (MMP), creating an immunosuppressive environment. TAMs inhibit cytotoxic CD8+ T cells through metabolic starvation via immunosuppressive metabolites like NO and ROS.
Multiple signaling pathways, such as the PD-1/PD-L1, SIRPA/CD47, and LILRB1, contribute to tumor immune escape and macrophage modulation. Additionally, TAMs play a role in promoting tumor growth, invasion, angiogenesis, and metastasis through the secretion of cytokines like IL-6, IL-10, and CCL2. VEGFs and MMPs further support tumor angiogenesis and invasion, emphasizing the multifaceted impact of TAMs on sarcoma progression.
TAMs in Different Sarcoma Subtypes
The presence and characteristics of TAMs vary among different subtypes of sarcomas. Specific markers, such as CD163, CD68, SIPRA, CD204, CD206, and CSF1R, are identified on the surface of TAMs in various sarcomas. For instance, SIRPA is observed in chordoma, dedifferentiated liposarcoma, angiosarcoma, and well-differentiated liposarcoma, while CD68 is prominent in pleomorphic liposarcoma, chordoma, chondrosarcoma, UPS, and angiosarcoma.
Prognostic Implications and Therapeutic Opportunities:
TAMs emerge as significant prognostic factors, correlating with poor overall survival and metastasis in sarcomas like chondrosarcoma, osteosarcoma, liposarcoma, UPS, and LMS. However, in certain sarcomas like ES or osteosarcoma, the infiltration of TAMs appears to be a favorable prognostic factor.
The clinical relevance of TAMs has sparked interest in potential therapeutic interventions. Ongoing clinical trials explore TAM-targeted therapies, including repolarization strategies, targeting activated TAMs, activating phagocytosis, and developing Toll-like receptor (TLR) antagonists. Pexidartinib and Trabectedin are already approved for sarcoma treatment, signaling progress in TAM-targeted therapies.
Conclusion
Despite significant strides in understanding TAMs and their role in sarcomas, much remains to be discovered. The heterogeneity of sarcomas, coupled with their rarity, presents challenges in pinpointing specific TAM markers and their interactions within TME. Nevertheless, TAMs stand out as a promising target for future sarcoma treatments, offering hope for more effective and personalized therapeutic strategies. Further research endeavors will undoubtedly shed light on the intricate mechanisms of TAMs, paving the way for innovative approaches in the battle against sarcomas.
The study findings were published in the peer reviewed journal: Cancers.
https://www.mdpi.com/2072-6694/15/21/5294
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