Promise and Challenges of T Cell Immunotherapy for Osteosarcoma

Abstract

The cure rate for metastatic or relapsed osteosarcoma has not substantially improved over the past decades despite the exploitation of multimodal treatment approaches, allowing long-term survival in less than 30% of cases. Patients with osteosarcoma often develop resistance to chemotherapeutic agents, where personalized targeted therapies should offer new hope. T cell immunotherapy as a complementary or alternative treatment modality is advancing rapidly in general, but its potential against osteosarcoma remains largely unexplored. Strategies incorporating immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) modified T cells, and T cell engaging bispecific antibodies (BsAbs) are being explored to tackle relapsed or refractory osteosarcoma. However, osteosarcoma is an inherently heterogeneous tumor, both at the intra- and inter-tumor level, with no identical driver mutations. It has a pro-tumoral microenvironment, where bone cells, stromal cells, neovasculature, suppressive immune cells, and a mineralized extracellular matrix (ECM) combine to derail T cell infiltration and its anti-tumor function. To realize the potential of T cell immunotherapy in osteosarcoma, an integrated approach targeting this complex ecosystem needs smart planning and execution. Herein, we review the current status of T cell immunotherapies for osteosarcoma, summarize the challenges encountered, and explore combination strategies to overcome these hurdles, with the ultimate goal of curing osteosarcoma with less acute and long-term side effects.

Keywords: T cell engaging bispecific antibody; T cell immunotherapy; chimeric antigen receptor; immune checkpoint inhibitors; myeloid-derived suppressor cells; osteosarcoma; tumor microenvironment; tumor-associated macrophage; vascular endothelial growth factor.

Figure 1

Tumor microenvironment of osteosarcoma. Osteosarcoma tumor tissues have large populations of tumors infiltrating myeloid cells (TIMs), including MDSCs and TAMs. Immunosuppressive TIMs and dense ECM around osteosarcoma cells impede T cell infiltration and cytotoxic activity. Tumor infiltrating T cells express PD-1, and the interactions between PD-1 and PD-L1 expressed on tumor cells and TIMs exhaust cytotoxic CD8(+) T cells, inducing tumor-immune tolerance. Regulatory T cells (Tregs) release TGF-β and convert ATP to adenosine via CD39 and CD73, inhibiting T cell cytotoxicity and promoting tumor progression [101]. M2 polarized TAMs and MDSCs also release immune-suppressive cytokines and chemokines including TGFβ, TNF-α, IL-10, prostaglandins, arginase, and VEGF, inducing osteosarcoma progression and immune evasion [102].