TY - JOUR
T1 - Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer
AU - Gumpert, Nofar
AU - Sagie, Shira
AU - Arnedo-Pac, Claudia
AU - Babu, Tomer
AU - Weller, Chen
AU - Gonzalez-Perez, Abel
AU - Wang, Yuan
AU - Todó, Lucas Michel
AU - Levy, Ronen
AU - Chen, Xi
AU - Greenberg, Polina
AU - Dayan-Rubinov, Maria
AU - Yakubovich, Elizabeta
AU - Wasserman-Bartov, Talya
AU - Zerbib, Mirie
AU - Gong, Jianhui
AU - Rebernick, Ryan J.
AU - Tercero, Anna Oliveira
AU - Muriel, Laura Agundez
AU - Benedek, Gil
AU - Kedmi, Merav
AU - Oren, Roni
AU - Ben-Dor, Shifra
AU - Levin, Yishai
AU - Troyanskaya, Olga G.
AU - Munzur, Aslı D.
AU - Wyatt, Alexander W.
AU - Cieslik, Marcin P.
AU - Quigley, David A.
AU - Van Allen, Eliezer M.
AU - Anandasabapathy, Niroshana
AU - Mateo, Joaquin
AU - Yang, Xinbo
AU - Martínez-Jiménez, Francisco
AU - Lopez-Bigas, Nuria
AU - Samuels, Yardena
N1 - Publisher Copyright:
© 2025 The Authors.
PY - 2026/2/1
Y1 - 2026/2/1
N2 - New approaches that generate long-lasting therapeutic responses in patients with therapy-resistant metastatic cancer are urgently needed. To address this challenge, we developed Spot Neoantigens in Metastases (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 neopeptides 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 (TCR) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y–specific TCRs are highly specific and kill prostate cancer cells presenting AR neopeptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for patients with mCRPC. Moreover, SpotNeoMet offers a systematic route to identify “HLA–peptide” pairs and their cognate TCRs across treatment-resistant cancers.
AB - New approaches that generate long-lasting therapeutic responses in patients with therapy-resistant metastatic cancer are urgently needed. To address this challenge, we developed Spot Neoantigens in Metastases (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 neopeptides 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 (TCR) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y–specific TCRs are highly specific and kill prostate cancer cells presenting AR neopeptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for patients with mCRPC. Moreover, SpotNeoMet offers a systematic route to identify “HLA–peptide” pairs and their cognate TCRs across treatment-resistant cancers.
UR - https://www.scopus.com/pages/publications/105029624061
UR - https://www.scopus.com/pages/publications/105029624061#tab=citedBy
U2 - 10.1158/2159-8290.cd-24-1213
DO - 10.1158/2159-8290.cd-24-1213
M3 - Article
C2 - 41056506
AN - SCOPUS:105029624061
SN - 2159-8274
VL - 16
SP - 250
EP - 269
JO - Cancer Discovery
JF - Cancer Discovery
IS - 2
ER -