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

Result code in 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>

Alternative codes found

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

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30204 - Oncology

Project

<a href="/en/project/LUAUS24120" target="_blank" >LUAUS24120: Synergistic targeting of hallmarks of cancer cells and their microenvironment</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

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

Name of the periodical

Cancer letters

ISSN

0304-3835

e-ISSN

1872-7980

Volume of the periodical

632

Issue of the periodical within the volume

NOV 1 2025

Country of publishing house

IE - IRELAND

Number of pages

14

Pages from-to

217969

UT code for WoS article

001547715900001

EID of the result in the Scopus database

2-s2.0-105012454817