Lightning Talk & Poster 28th Annual Lorne Proteomics Symposium 2023

Exploring the phospho-immunopeptidome in haematological malignancy and their specific T cell receptors in cancer precision medicine (#22)

Kirti Pandey 1 , Sri H Ramarathinam 1 , Anthony Schwarer 2 , Jan Petersen 1 , Nicole Mifsud 1 , Jamie Rossjohn 1 , Anthony W Purcell 1
  1. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  2. Eastern Health Clinical School, Melbourne, VIC, Australia

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.