Regulation and improvement of host immune response in osteosarcoma

Osteosarcoma (OS) is the most common primary bone malignancy, predominantly affecting children and adolescents. About 80% of OS patients will develop metastasis within 10 years, and approximately 40% of these patients will succumb to their disease despite intense, debilitating treatments. The unrewarding clinical outcomes have landed this disease among the “most wanted” for development of new and effective therapies. Immunotherapy is dramatically changing how we treat patients with cancer. These novel antibody-based therapies do not target cancer cells directly; instead, they block immune checkpoint molecules such as CTLA-4 and PD-1, which inhibit host antitumor T-cell responses. Tumors use a variety of mechanisms to evade, deceive and suppress the host immune system. MicroRNAs (miRNAs), which repress gene expression through translational repression or posttranscriptional degradation, are secreted from cells in the tumor microenvironment (TME) in extracellular vesicles (EVs) and can perform their regulatory function in recipient cells such as T cells. We have uncovered novel, tumor-intrinsic factors that mold the tumor-immune environment. In particular, a family of conserved small RNAs (microRNAs) secreted in tumor-derived extracellular vesicles lead to destabilization of the CD28 co-receptor when T cells take them up. T cells become activated after encountering tumor antigens, primarily in lymph nodes, in a CD28-dependent process that results in proliferation and differentiation.


Recent publications

Sarver A, Mills L, Makielski K, Temiz N, Wang J, Spector L, Subramanian S, Modiano J. (2023). Distinct mechanisms of PTEN inactivation in dogs and humans highlight convergent molecular events that drive cell division in the pathogenesis of osteosarcoma. Cancer Genetics. 276-277. 10.1016/j.cancergen.2023.05.001. 

Makielski KM, Donnelly AJ, Khammanivong A, et al. Development of an exosomal gene signature to detect residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning. Lab Invest. 2021;101(12):1585-1596. doi:10.1038/s41374-021-00655-w

Mills LJ, Scott MC, Shah P, et al. Comparative analysis of genome-wide DNA methylation identifies patterns that associate with conserved transcriptional programs in osteosarcoma [published online ahead of print, 2020 Oct 27]. Bone. 2020;115716. doi:10.1016/j.bone.2020.115716

Scott MC, Temiz NA, Sarver AE, LaRue RS, Rathe SK, Varshney J, Wolf NK, Moriarity BS, Spector LG, Modiano JF, Largaespada DA, Subramanian S, Sarver AL. Comparative transcriptome analysis quantifies immune cell transcript levels metastatic progression and survival in osteosarcoma. Cancer Research 2018 78: 326-337