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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F25%3A00638780" target="_blank" >RIV/86652036:_____/25:00638780 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14110/25:00141883 RIV/00216208:11110/25:10515618 RIV/00216208:11310/25:10515618 RIV/00159816:_____/25:00082417

Výsledek na webu

<a href="https://doi.org/10.1016/j.canlet.2025.217969" target="_blank" >https://doi.org/10.1016/j.canlet.2025.217969</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.canlet.2025.217969" target="_blank" >10.1016/j.canlet.2025.217969</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

<a href="/cs/project/LUAUS24120" target="_blank" >LUAUS24120: Synergické cílení klíčových znaků nádorových buněk a jejich mikroprostředí</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cancer letters

ISSN

0304-3835

e-ISSN

1872-7980

Svazek periodika

632

Číslo periodika v rámci svazku

NOV 1 2025

Stát vydavatele periodika

IE - Irsko

Počet stran výsledku

14

Strana od-do

217969

Kód UT WoS článku

001547715900001

EID výsledku v databázi Scopus

2-s2.0-105012454817