Haematological malignancy (HM) is an umbrella term used for neoplasms originating in haematopoietic and lymphoid tissues. Treatment guidelines for HM includes induction therapy or allogeneic hematopoietic cell transplantation (allo-HCT). Although allo-HCT is considered an optimal approach, transplant-related mortality is seen in significant numbers in HM patients. Hence alternative forms of treatment must be explored. Dysregulated phosphorylation at serine, threonine and tyrosine residues is a hallmark of neoplastic transformations. Phosphorylation at these residues is retained even after proteins are processed by human leukocyte antigen (HLA) class I machinery and presented as peptides on cell surface of cancer cells (known as the immunopeptidome). These neoantigens can be targeted for immunotherapies such as T cell receptor (TCR) based vaccines, chimeric antigenic receptor T cells and bispecific antibodies. In this study we have used mass spectrometry to identify the phospho-immunopeptidome in HM cell lines and patient bone marrow samples. The immunogenicity of some of the phosphopeptide was assessed in patient peripheral blood mononuclear cells.
A total of 81,027 HLA class I peptides were identified from 3 cell lines and 4 clinical bone marrow aspirates. A total of 1,733 phosphopeptides including rare tyrosine phosphorylated (restricted to HLA A2) were detected. The study reports for the first time of identifying TCRs specific for phosphopeptides presented by HLA-A2 and -B07 in HM patients.
Since phosphorylation is driving force across several tumour malignancies, identification of phosphopeptide specific TCRs will aid in development of novel immunotherapeutic approaches.