Development of succinate dehydrogenase subunit B-deficient
tumor models for preclinical immunotherapy testing

J 2025

Development of succinate dehydrogenase subunit B-deficient tumor models for preclinical immunotherapy testing

VANOVA, Katerina Hadrava; Ondrej UHER; Michal KRAUS; Sona MIKLOVICOVA; Kateřina HÖNIGOVÁ et. al.

Základní údaje

Originální název

Development of succinate dehydrogenase subunit B-deficient tumor models for preclinical immunotherapy testing

Autoři

VANOVA, Katerina Hadrava; Ondrej UHER; Michal KRAUS; Sona MIKLOVICOVA; Kateřina HÖNIGOVÁ (203 Česká republika, domácí); Stanislaw GWIEZDZINSKI; Timothy J GARRETT; Hans GHAYEE; Michal MASAŘÍK (203 Česká republika, domácí); Herui WANG; Zhengping ZHUANG; Jiri NEUZIL; Chunzhang YANG a Karel PACAK

Vydání

Cancer letters, CLARE, ELSEVIER IRELAND LTD, 2025, 0304-3835

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 10.100 v roce 2024

Organizační jednotka

Lékařská fakulta

DOI

https://doi.org/10.1016/j.canlet.2025.217969

UT WoS

001547715900001

EID Scopus

2-s2.0-105012454817

Klíčová slova anglicky

Succinate dehydrogenase subunit B; Pheochromocytoma; Paraganglioma; Renal cell carcinoma; Immunotherapy; Metastasis; Tumor growth

Štítky

14110518, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 1. 9. 2025 09:44, Mgr. Tereza Miškechová

Anotace

V originále

Immunotherapy has advanced the treatment landscape for many challenging cancers by harnessing the immune system to eliminate tumor cells. However, its efficacy in rare tumors such as pheochromocytoma and paraganglioma (PCC/PGL), particularly those with succinate dehydrogenase B (SDHB) mutations, remains underexplored. These tumors often exhibit complex tumor microenvironments and immune evasion mechanisms, and their low incidence hinders clinical trials development. Together, these challenges underscore the need for robust preclinical models that closely mirror human disease and support therapeutic discovery. In this study, we developed and characterized murine models of SDHB-deficient tumors using CRISPRmediated gene editing in pheochromocytoma (MPC and MTT) and renal carcinoma (RenCa) cell lines. These models recapitulate key metabolic and immunological features of human SDHB-mutated tumors, which exhibit loss of SDHB protein expression, providing a relevant platform for evaluating immunotherapeutic strategies. We subsequently tested intratumoral immunotherapy with Mannan-BAM, TLR ligands, and an Anti-CD40 antibody (MBTA), a combination designed to overcome tumor-induced immune suppression. Our results indicate that SDHB-deficient PCC tumors exhibit increased antigen presentation and strong immune activation, leading to rejection or delayed progression in immunocompetent mice. In contrast, Sdhb knockout RenCa tumors consistently formed, allowing therapeutic testing. MBTA therapy effectively eradicated these tumors, prevented metastasis, and induced long-term immune memory. These findings highlight the value of genetically engineered, tissue-specific murine models in predicting immunotherapy outcomes in rare cancers. Moreover, they support the therapeutic potential of MBTA for treating SDHB-deficient renal cell carcinoma and provide a rationale for further translational studies.

Návaznosti

LUAUS24120, projekt VaV

Název: Synergické cílení klíčových znaků nádorových buněk a jejich mikroprostředí

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Synergické cílení klíčových znaků nádorových buněk a jejich mikroprostředí, INTER-ACTION (USA)

Citovat

VANOVA, Katerina Hadrava; Ondrej UHER; Michal KRAUS; Sona MIKLOVICOVA; Kateřina HÖNIGOVÁ; Stanislaw GWIEZDZINSKI; Timothy J GARRETT; Hans GHAYEE; Michal MASAŘÍK; Herui WANG; Zhengping ZHUANG; Jiri NEUZIL; Chunzhang YANG a Karel PACAK. Development of succinate dehydrogenase subunit B-deficient tumor models for preclinical immunotherapy testing. Cancer letters. CLARE: ELSEVIER IRELAND LTD, 2025, roč. 632, November 2025, s. 1-14. ISSN 0304-3835. Dostupné z: https://doi.org/10.1016/j.canlet.2025.217969.

@article{2514909,
   author = {Vanova, Katerina Hadrava and Uher, Ondrej and Kraus, Michal and Miklovicova, Sona and Hönigová, Kateřina and Gwiezdzinski, Stanislaw and Garrett, Timothy J and Ghayee, Hans and Masařík, Michal and Wang, Herui and Zhuang, Zhengping and Neuzil, Jiri and Yang, Chunzhang and Pacak, Karel},
   article_location = {CLARE},
   article_number = {November 2025},
   doi = {https://doi.org/10.1016/j.canlet.2025.217969},
   keywords = {Succinate dehydrogenase subunit B; Pheochromocytoma; Paraganglioma; Renal cell carcinoma; Immunotherapy; Metastasis; Tumor growth},
   language = {eng},
   issn = {0304-3835},
   journal = {Cancer letters},
   title = {Development of succinate dehydrogenase subunit B-deficient tumor models for preclinical immunotherapy testing},
   url = {https://www.sciencedirect.com/science/article/pii/S0304383525005385?via%3Dihub},
   volume = {632},
   year = {2025}
}

TY  - JOUR
ID  - 2514909
AU  - Vanova, Katerina Hadrava - Uher, Ondrej - Kraus, Michal - Miklovicova, Sona - Hönigová, Kateřina - Gwiezdzinski, Stanislaw - Garrett, Timothy J - Ghayee, Hans - Masařík, Michal - Wang, Herui - Zhuang, Zhengping - Neuzil, Jiri - Yang, Chunzhang - Pacak, Karel
PY  - 2025
TI  - Development of succinate dehydrogenase subunit B-deficient tumor models for preclinical immunotherapy testing
JF  - Cancer letters
VL  - 632
IS  - November 2025
SP  - 1-14
EP  - 1-14
PB  - ELSEVIER IRELAND LTD
SN  - 03043835
KW  - Succinate dehydrogenase subunit B
KW  - Pheochromocytoma
KW  - Paraganglioma
KW  - Renal cell carcinoma
KW  - Immunotherapy
KW  - Metastasis
KW  - Tumor growth
UR  - https://www.sciencedirect.com/science/article/pii/S0304383525005385?via%3Dihub
N2  - Immunotherapy has advanced the treatment landscape for many challenging cancers by harnessing the immune system to eliminate tumor cells. However, its efficacy in rare tumors such as pheochromocytoma and paraganglioma (PCC/PGL), particularly those with succinate dehydrogenase B (SDHB) mutations, remains underexplored. These tumors often exhibit complex tumor microenvironments and immune evasion mechanisms, and their low incidence hinders clinical trials development. Together, these challenges underscore the need for robust preclinical models that closely mirror human disease and support therapeutic discovery. In this study, we developed and characterized murine models of SDHB-deficient tumors using CRISPRmediated gene editing in pheochromocytoma (MPC and MTT) and renal carcinoma (RenCa) cell lines. These models recapitulate key metabolic and immunological features of human SDHB-mutated tumors, which exhibit loss of SDHB protein expression, providing a relevant platform for evaluating immunotherapeutic strategies. We subsequently tested intratumoral immunotherapy with Mannan-BAM, TLR ligands, and an Anti-CD40 antibody (MBTA), a combination designed to overcome tumor-induced immune suppression. Our results indicate that SDHB-deficient PCC tumors exhibit increased antigen presentation and strong immune activation, leading to rejection or delayed progression in immunocompetent mice. In contrast, Sdhb knockout RenCa tumors consistently formed, allowing therapeutic testing. MBTA therapy effectively eradicated these tumors, prevented metastasis, and induced long-term immune memory. These findings highlight the value of genetically engineered, tissue-specific murine models in predicting immunotherapy outcomes in rare cancers. Moreover, they support the therapeutic potential of MBTA for treating SDHB-deficient renal cell carcinoma and provide a rationale for further translational studies.
ER  -

VANOVA, Katerina Hadrava; Ondrej UHER; Michal KRAUS; Sona MIKLOVICOVA; Kateřina HÖNIGOVÁ; Stanislaw GWIEZDZINSKI; Timothy J GARRETT; Hans GHAYEE; Michal MASAŘÍK; Herui WANG; Zhengping ZHUANG; Jiri NEUZIL; Chunzhang YANG a Karel PACAK. Development of succinate dehydrogenase subunit B-deficient tumor models for preclinical immunotherapy testing. \textit{Cancer letters}. CLARE: ELSEVIER IRELAND LTD, 2025, roč.~632, November 2025, s.~1-14. ISSN~0304-3835. Dostupné z: https://doi.org/10.1016/j.canlet.2025.217969.

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