T-cell infiltration profile in musculoskeletal tumors

Immunotherapy of musculoskeletal tumors remains clinically challenging and requires the development of gene-engineered/adoptive exogenous immune cells or the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Recently, endogenous B-cell infiltration into tumor microenvironments appears to be an essential promising prognostic factor controlling tumor progression in musculoskeletal malignancy. Here, we explored the level of T-cell infiltration by analyzing expression profiles of CD3E, CD4, and CD8A in 1366 patients and 23 histological types. The data revealed that CD3E and CD8A expressions were predominantly inhibited in bone tumors when compared with normal bone. CD4 expression was upregulated in limited types of tumors, including chondrosarcoma and giant cell tumor of bone, whereas other tumors demonstrated relatively lower expressions. Similarly, regarding soft tissue sarcoma, the expression of T-cell-related molecules was largely inhibited. Only in patients with rhabdomyosarcoma, CD3E and CD8A expressions were significantly upregulated, showing the nature of immune-active tumor. To visualize the immunological microenvironment of rhabdomyosarcoma, we have developed a novel software aimed at analyzing numerous cell-to-cell and ligand-to-receptor interactions, that is, Environmentome. It has led to the identification of molecular interactions between CD8⁺ T cell and rhabdomyosarcoma via Galectin3-LAG3 binding, which is a novel immune checkpoint recently identified. In conclusion, musculoskeletal tumors may be defined as immune-quiescent tumors, whereby targeting Galectin-3 and/or immune-infiltrative agents could be crucial in these immunologically noninflamed musculoskeletal tumors, accelerating immunotherapeutic response.