Understanding micrometastatic disease and Anoikis resistance in ewing family of tumors and osteosarcoma

Understanding micrometastatic disease and Anoikis resistance in ewing family of tumors and osteosarcoma. Oncologist 2010;15:627C635. strategy. Keywords: programmed death receptor-1, PD-L1, osteosarcoma, antibody therapy, metastatic osteosarcoma Osteosarcoma remains the most common pediatric bone malignancy, and is the eighth most common child years malignancy overall.1,2 Osteosarcoma develops from bone osteoblasts, typically during periods of quick bone growth, with a median occurrence at 14 years of age.3 Main tumors HS-10296 hydrochloride typically occur in long tubular bones, with a small percentage of main tumors originating in the axial skeleton.4 Chemotherapy, often accompanied by surgical resection, can improve the outcome for patients with localized tumors, with a 5-12 months event-free survival for treated patients of 65%C70%.5C7 Unfortunately, 25%C30% of osteosarcoma patients present with metastatic disease at diagnosis and patients with nonmetastatic osteosarcoma at initial presentation often develop metastatic disease.8,9 Osteosarcoma metastases most often occur in the lungs followed by other bones. Chemotherapy, with or without surgical resection, is not effective against metastatic osteosarcoma with a 5-12 months event-free survival for these patients of <20%.5C7 Therefore, new efficacious treatment modalities for metastatic osteosarcoma are needed to improve patient prognoses. T cells have the potential to potently and specifically reject cancerous cells while avoiding the unwanted side effects seen in other tumor therapy strategies. In many settings, cancer patients generate T-cell responses against their respective tumors, and tumor-reactive T cells are able to infiltrate the tumor to slow progression or eliminate the tumor.10,11 However, during tumor equilibrium or progression, tumor-reactive T cells often become tolerized, limiting their ability to reject tumors. This tolerance, often termed exhaustion, is characterized by a progressive decrease in T-cell proliferation, cytokine production, and cytotoxic function.12 T-cell exhaustion was first shown in the lymphocytic choriomeningitis computer virus (LCMV) mouse model of chronic viral contamination, and has since been confirmed in numerous clinical and experimental tumor settings including hepatocellular carcinoma, ovarian malignancy, Hodgkin lymphoma, urothelial cell carcinoma, pancreatic malignancy, renal cell carcinoma, malignant melanoma, acute myeloid leukemia, head and neck squamous cell carcinoma, and Friend leukemia virusCinduced tumors.13C20 Thus, many next-generation immunotherapeutic approaches for targeting chemotherapy-resistant and radiation-resistant tumors are aimed at reinvigorating T-cell responses to mediate potent and specific tumor rejection. Numerous lines of evidence suggest that tumor-reactive cytotoxic T lymphocytes (CTLs) are induced during the development of metastatic osteosarcoma but become worn out: (1) large numbers of CTLs infiltrate metastatic osteosarcomas but are unable to mediate tumor rejection21,22; (2) polymorphisms associated with increased expression of CTLA4, a potent T-cell inhibitory protein, are associated with higher risk of developing osteosarcoma4; (3) metastatic tumors, but not main osteosarcoma, have increased expression of ligands for T-cell Ig/mucin molecule 3 (TIM3), which has IL1R1 antibody been shown in other tumor settings to inhibit the function of infiltrating CTLs, leading to tumor progression23,24; and (4) B7-H3 expression, a costimulatory protein involved in tumor immune escape from T cells, inversely correlates with CTLs infiltration in human osteosarcoma, and is indicative of poor prognosis in osteosarcoma patients.25C28 T-cell exhaustion has been shown to be due, at least in HS-10296 hydrochloride part, to expression of inhibitory proteins on tumor-reactive T cells that are engaged by their respective ligands on tumor cells.29,30 Programmed death receptor-1 (PD-1, CD279) expression on tumor-specific CTLs, which binds PD-1 ligand (PD-L1, CD274) on tumor cells, has been shown to inhibit T-cell function leading to tumor progression in a variety of experimental and clinical tumor HS-10296 hydrochloride settings, including hepatocellular carcinoma, ovarian malignancy, Hodgkin lymphoma, urothelial cell carcinoma, pancreatic malignancy, renal cell carcinoma, malignant melanoma, acute myeloid leukemia, and head and neck squamous cell carcinoma. 14C20 Antibody blockade of PD-1/PD-L1 interactions in experimental tumor settings can effectively restore CTLs function and enhance immune-mediated.