Targeting Tumor-Associated Macrophages in the Pediatric Sarcoma Tumor Microenvironment

Abstract

For many pediatric sarcoma patients, multi-modal therapy including chemotherapy, radiation, and surgery is sufficient to cure their disease. However, event-free and overall survival rates for patients with more advanced disease are grim, necessitating the development of novel therapeutic approaches. Within many pediatric sarcomas, the normal immune response, including recognition and destruction of cancer cells, is lost due to the highly immune suppressive tumor microenvironment (TME). In this setting, tumor cells evade immune detection and capitalize on the immune suppressed microenvironment, leading to unchecked proliferation and metastasis. Recent preclinical and clinical approaches are aimed at understanding this immune suppressive microenvironment and employing cancer immunotherapy in an attempt to overcome this, by renewing the ability of the immune system to recognize and destroy cancer cells. While there are several factors that drive the attenuation of immune responses in the sarcoma TME, one of the most remarkable are tumor associated macrophage (TAMs). TAMs suppress immune cytolytic function, promote tumor growth and metastases, and are generally associated with a poor prognosis in most pediatric sarcoma subtypes. In this review, we summarize the mechanisms underlying TAM-facilitated immune evasion and tumorigenesis and discuss the potential therapeutic application of TAM-focused drugs in the treatment of pediatric sarcomas.

Adoptive Cell Therapy in Pediatric and Young Adult Solid Tumors: Current Status and Future Directions

“…Tumor-associated cytokines such as IL-10, IL-4, IL-13 and TGF-β promote polarization towards an immunosuppressive M2 phenotype. M2 TAMs promote tumor progression through mechanisms including angiogenesis, extracellular matrix (ECM) remodeling and regulatory T-cell recruitment ( 72 ). This M1/M2 classification is an oversimplification, however induction of an M1-like, anti-tumor phenotype is important for the success of myeloid-based ACT.…”

The Role of IGF/IGF-IR-Signaling and Extracellular Matrix Effectors in Bone Sarcoma Pathogenesis

“…Indeed, they intermix with tumor cells, immune cells, and other cell types in a tumor-surrounding pseudocapsule. Furthermore, the function of nonmalignant cells in sarcoma stroma is well less characterized [93]. Moreover, pediatric and adult sarcomas exhibit distinct characteristics regarding tumor tissue structure [93].…”

“…Furthermore, the function of nonmalignant cells in sarcoma stroma is well less characterized [93]. Moreover, pediatric and adult sarcomas exhibit distinct characteristics regarding tumor tissue structure [93]. Notably, both tumor and stromal cells produce ECM components that offer structural support and modulate tumor cells' interaction with the TME.…”

Targeting tumor microenvironment and metastasis in children with solid tumors

“…Relative to adult tumors, pediatric solid tumors are typically characterized by low mutational burden, low neoantigen expression, major histocompatibility complex (MHC) loss, and poor infiltration by T cells [8][9][10][11]. By contrast, myeloid cells, such as tumor-associated macrophages (TAM) are abundant in many pediatric solid tumor types and are associated with inferior prognosis [11][12][13]. Myeloid cells are highly plastic and can acquire immune-stimulatory or immune-suppressive phenotypes in response to factors present in the TME.…”

“…Myeloid cells are highly plastic and can acquire immune-stimulatory or immune-suppressive phenotypes in response to factors present in the TME. Immune-suppressive myeloid cells in the TME dampen effector T-cell responses, inhibit antigen presentation, and promote vasculogenesis and ECM remodeling [13,14] (Fig. 1).…”