Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer

Gumpert, Nofar; Sagie, Shira; Arnedo Pac, Claudia; Babu, Tomer; Weller, Chen; Gonzalez Perez, Abel David; Wang, Yuan; Todó, Lucas Michel; Levy, Ronen; Chen, Xi; Greenberg, Polina; Dayan-Rubinov, Maria; Yakubovich, Elizabeta; Wasserman-Bartov, Talya; Zerbib, Mirie; Gong, Jianhui; Rebernick, Ryan J.; Oliveira Tercero, Anna; Agundez Muriel, Laura; Benedek, Gil; Kedmi, Merav; Oren, Roni; Ben-Dor, Shifra; Levin, Yishai; Troyanskaya, Olga G.; Munzur, Aslı D.; Wyatt, Alexander W.; Cieslik, Marcin P.; Quigley, David A.; Van Allen, Eliezer M.; Anandasabapathy, Niroshana; Mateo, Joaquin; Yang, Xinbo; Martínez Jiménez, Francisco; López Bigas, Núria; Samuels, Yardena

Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer

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 prese...

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Autores:	Gumpert, Nofar, Sagie, Shira, Arnedo Pac, Claudia, Babu, Tomer, Weller, Chen, Gonzalez Perez, Abel David, Wang, Yuan, Todó, Lucas Michel, Levy, Ronen, Chen, Xi, Greenberg, Polina, Dayan-Rubinov, Maria, Yakubovich, Elizabeta, Wasserman-Bartov, Talya, Zerbib, Mirie, Gong, Jianhui, Rebernick, Ryan J., Oliveira Tercero, Anna, Agundez Muriel, Laura, Benedek, Gil, Kedmi, Merav, Oren, Roni, Ben-Dor, Shifra, Levin, Yishai, Troyanskaya, Olga G., Munzur, Aslı D., Wyatt, Alexander W., Cieslik, Marcin P., Quigley, David A., Van Allen, Eliezer M., Anandasabapathy, Niroshana, Mateo, Joaquin, Yang, Xinbo, Martínez Jiménez, Francisco, López Bigas, Núria, Samuels, Yardena
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2026
País:	España
Institución:	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:	Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:	oai:recercat.cat:2445/227763
Acceso en línea:	https://hdl.handle.net/2445/227763
Access Level:	acceso abierto
Palabra clave:	Metàstasi Proteïnes supressores de tumors Càncer d'úter Metastasis Tumor suppressor protein Uterine cancer

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spelling	Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate CancerGumpert, NofarSagie, ShiraArnedo Pac, ClaudiaBabu, TomerWeller, ChenGonzalez Perez, Abel DavidWang, YuanTodó, Lucas MichelLevy, RonenChen, XiGreenberg, PolinaDayan-Rubinov, MariaYakubovich, ElizabetaWasserman-Bartov, TalyaZerbib, MirieGong, JianhuiRebernick, Ryan J.Oliveira Tercero, AnnaAgundez Muriel, LauraBenedek, GilKedmi, MeravOren, RoniBen-Dor, ShifraLevin, YishaiTroyanskaya, Olga G.Munzur, Aslı D.Wyatt, Alexander W.Cieslik, Marcin P.Quigley, David A.Van Allen, Eliezer M.Anandasabapathy, NiroshanaMateo, JoaquinYang, XinboMartínez Jiménez, FranciscoLópez Bigas, NúriaSamuels, YardenaMetàstasiProteïnes supressores de tumorsCàncer d'úterMetastasisTumor suppressor proteinUterine cancerNew 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.Significance: As the emergence of resistance to targeted treatments in patients with metastatic cancer, there is an urgent need for innovative therapeutic approaches for this population. Our study provides a new analytic framework to identify neoantigens from treatment-resistant mutations and a proof-of-concept T cell-based immunotherapy treatment for mCRPC.American Association for Cancer Research2026202620262026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion20 p.application/pdfhttps://hdl.handle.net/2445/227763Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1158/2159-8290.cd-24-1213Cancer Discovery, 2026, vol. 16, num. 2, p. 250-269https://doi.org/10.1158/2159-8290.cd-24-1213cc-by-nc-nd (c) Gumpert, Nofar et al., 2025https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/2277632026-05-29T05:05:01Z
dc.title.none.fl_str_mv	Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer
title	Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer
spellingShingle	Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer Gumpert, Nofar Metàstasi Proteïnes supressores de tumors Càncer d'úter Metastasis Tumor suppressor protein Uterine cancer
title_short	Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer
title_full	Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer
title_fullStr	Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer
title_full_unstemmed	Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer
title_sort	Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer
dc.creator.none.fl_str_mv	Gumpert, Nofar Sagie, Shira Arnedo Pac, Claudia Babu, Tomer Weller, Chen Gonzalez Perez, Abel David Wang, Yuan Todó, Lucas Michel Levy, Ronen Chen, Xi Greenberg, Polina Dayan-Rubinov, Maria Yakubovich, Elizabeta Wasserman-Bartov, Talya Zerbib, Mirie Gong, Jianhui Rebernick, Ryan J. Oliveira Tercero, Anna Agundez Muriel, Laura Benedek, Gil Kedmi, Merav Oren, Roni Ben-Dor, Shifra Levin, Yishai Troyanskaya, Olga G. Munzur, Aslı D. Wyatt, Alexander W. Cieslik, Marcin P. Quigley, David A. Van Allen, Eliezer M. Anandasabapathy, Niroshana Mateo, Joaquin Yang, Xinbo Martínez Jiménez, Francisco López Bigas, Núria Samuels, Yardena
author	Gumpert, Nofar
author_facet	Gumpert, Nofar Sagie, Shira Arnedo Pac, Claudia Babu, Tomer Weller, Chen Gonzalez Perez, Abel David Wang, Yuan Todó, Lucas Michel Levy, Ronen Chen, Xi Greenberg, Polina Dayan-Rubinov, Maria Yakubovich, Elizabeta Wasserman-Bartov, Talya Zerbib, Mirie Gong, Jianhui Rebernick, Ryan J. Oliveira Tercero, Anna Agundez Muriel, Laura Benedek, Gil Kedmi, Merav Oren, Roni Ben-Dor, Shifra Levin, Yishai Troyanskaya, Olga G. Munzur, Aslı D. Wyatt, Alexander W. Cieslik, Marcin P. Quigley, David A. Van Allen, Eliezer M. Anandasabapathy, Niroshana Mateo, Joaquin Yang, Xinbo Martínez Jiménez, Francisco López Bigas, Núria Samuels, Yardena
author_role	author
author2	Sagie, Shira Arnedo Pac, Claudia Babu, Tomer Weller, Chen Gonzalez Perez, Abel David Wang, Yuan Todó, Lucas Michel Levy, Ronen Chen, Xi Greenberg, Polina Dayan-Rubinov, Maria Yakubovich, Elizabeta Wasserman-Bartov, Talya Zerbib, Mirie Gong, Jianhui Rebernick, Ryan J. Oliveira Tercero, Anna Agundez Muriel, Laura Benedek, Gil Kedmi, Merav Oren, Roni Ben-Dor, Shifra Levin, Yishai Troyanskaya, Olga G. Munzur, Aslı D. Wyatt, Alexander W. Cieslik, Marcin P. Quigley, David A. Van Allen, Eliezer M. Anandasabapathy, Niroshana Mateo, Joaquin Yang, Xinbo Martínez Jiménez, Francisco López Bigas, Núria Samuels, Yardena
author2_role	author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Metàstasi Proteïnes supressores de tumors Càncer d'úter Metastasis Tumor suppressor protein Uterine cancer
topic	Metàstasi Proteïnes supressores de tumors Càncer d'úter Metastasis Tumor suppressor protein Uterine cancer
description	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.Significance: As the emergence of resistance to targeted treatments in patients with metastatic cancer, there is an urgent need for innovative therapeutic approaches for this population. Our study provides a new analytic framework to identify neoantigens from treatment-resistant mutations and a proof-of-concept T cell-based immunotherapy treatment for mCRPC.
publishDate	2026
dc.date.none.fl_str_mv	2026 2026 2026 2026
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/2445/227763
url	https://hdl.handle.net/2445/227763
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Reproducció del document publicat a: https://doi.org/10.1158/2159-8290.cd-24-1213 Cancer Discovery, 2026, vol. 16, num. 2, p. 250-269 https://doi.org/10.1158/2159-8290.cd-24-1213
dc.rights.none.fl_str_mv	cc-by-nc-nd (c) Gumpert, Nofar et al., 2025 https://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	cc-by-nc-nd (c) Gumpert, Nofar et al., 2025 https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	20 p. application/pdf
dc.publisher.none.fl_str_mv	American Association for Cancer Research
publisher.none.fl_str_mv	American Association for Cancer Research
dc.source.none.fl_str_mv	Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona)) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str	Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str	Recercat. Dipósit de la Recerca de Catalunya
collection	Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Recurrent Immunogenic Neoantigens and Their Cognate T-cell Receptors in Treatment-Resistant Metastatic Prostate Cancer

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