Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. It is due to the growth of neoplastic B cells in the bone marrow, blood, and lymphoid tissues. People with relapsed/refractory high-risk CLL do not respond to conventional treatments. A possible valuable strategy to design T-cell−based treatment involves the receptor tyrosine kinase-like orphan receptor 1 (ROR1). ROR1 mRNA is found to be highly expressed in CLL cells; however, it is not found to be expressed in other bone marrow–derived cells, including blood cells, or normal adult non-hematopoietic cells. Higher expression of ROR1 in CLL cells was correlated with lower CLL survival. Therefore, ROR1 may play a key role in the progression of CLL.
A study was conducted to uncover an ROR1 peptide that can be used as a target for T-cell–based treatment for CLL patients. Mass spectrometry–based analyses were performed on HLA ligands from peripheral blood mononuclear cells of patients sharing HLA-A*03:01 and HLA-B*07:02. A natural ROR1-derived nonamer was identified and was found to be present on nearly 30% of HLA-matched CLL cell samples, as well as on renal and ovarian cell lines. When exploring a database of HLA class I ligandomes of normal tissue, the identified nonamer was not found.
The researchers generated ROR1 peptide–specific CD8+ cytotoxic T cell clones. T cells were isolated from peripheral blood of healthy donors and cultured with dendritic cells pulsed with the nonamer. Flow cytometry was used to detect the ROR1 peptide–specific cytotoxic T cells. A flow cytometry–based killing assay was used to determine the cytotoxic activity of the ROR1 peptide–specific T-cell clones. The clones were found to efficiently lyse ROR1 CLL cells.
Overall, a naturally presented ROR1 peptide found in the CLL ligandome was not found in the ligandome of various normal tissue cells studied. ROR1-specific cytotoxic T-cell clones had the capacity to lyse ROR1 CLL, renal, and ovarian cancer line cells. Taken together, the results indicate that the ROR1 peptide may serve as viable target for the design of T-cell–based immunotherapies for CLL and other cancers.
Heidenreich, F., Rücker-Braun, E., Walz, J., Eugster, A., Kühn, D., & Dietz, S. et al. (2017). Mass spectrometry-based identification of a naturally presented receptor tyrosine kinase-like orphan receptor 1-derived epitope recognized by CD8 + cytotoxic T cells . Haematologica, 102(11), e460-e464. doi:10.3324/haematol.2017.167312