Recurrent immunogenic neoantigens and their cognate T-cell receptors in treatment-resistant metastatic prostate cancer

ABSTRACT: New approaches that generate long-lasting therapeutic responses in therapy-resistant metastatic cancer patients are urgently needed. To address this challenge, we developed SpotNeoMet, a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neo-peptides presented by common HLAs. Using HLA-immunopeptidomics, we discovered three novel neopeptides derived from Androgen Receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCRs) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y specific TCRs are highly specific and kill prostate cancer cells presenting AR neo-peptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for mCRPC patients. Moreover, SpotNeoMet offers a systematic route to identify 'HLA-peptide' pairs and their cognate TCRs across treatment-resistant cancers.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Lncap Cell, Epithelial Cell, Lcl-721 Cell

DISEASE(S): Castration-resistant Prostate Carcinoma

SUBMITTER: Nofar Gumpert  

LAB HEAD: Yardena Samuels

PROVIDER: PXD055544 | Pride | 2025-10-03

REPOSITORIES: Pride