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KALRN mutations promote antitumor immunity and immunotherapy response in cancer
Mengyuan Li1,2,3, Yuxiang Ma4, You Zhong4
1Biomedical Informatics Research Lab,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Background:
kalirin RhoGEF kinase (KALRN) is mutated in a wide range of cancers. Nevertheless, the association between KALRN mutations and the pathogenesis of cancer remains unexplored. Identification of biomarkers for cancer immunotherapy response is crucial because immunotherapies only show beneficial effects in a subset of patients with cancer.
Methods:
We explored the correlation between KALRN mutations and antitumor immunity in 10 cancer cohorts from The Cancer Genome Atlas program by the bioinformatics approach. Moreover, we verified the findings from the bioinformatics analysis with in vitro and in vivo experiments. We explored the correlation between KALRN mutations and immunotherapy response in five cancer cohorts receiving immune checkpoint blockade therapy.
Results:
Antitumor immune signatures were more enriched in KALRN-mutated than KALRN-wildtype cancers. Moreover, KALRN mutations displayed significant correlations with increased tumor mutation burden and the microsatellite instability or DNA damage repair deficiency genomic properties, which may explain the high antitumor immunity in KALRN-mutated cancers. Also, programmed cell death 1 ligand (PD-L1) expression was markedly upregulated in KALRN-mutated versus KALRN-wildtype cancers. The increased antitumor immune signatures and PD-L1 expression in KALRN-mutated cancers may favor the response to immune checkpoint blockade therapy in this cancer subtype, as evidenced in five cancer cohorts receiving antiprogrammed cell death protein 1 (PD-1)/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy. Furthermore, the significant association between KALRN mutations and increased antitumor immunity was associated with the fact that KALRN mutations compromised the function of KALRN in targeting Rho GTPases for the regulation of DNA damage repair pathways. In vitro and in vivo experiments validated the association of KALRN deficiency with antitumor immunity and the response to immune checkpoint inhibitors.
Conclusions:
The KALRN mutation is a useful biomarker for predicting the response to immunotherapy in patients with cancer.
Insights
Kalirin RhoGEF kinase (KALRN) mutations are linked to enhanced antitumor immunity and may predict immunotherapy response in cancer patients. This discovery highlights KALRN as a potential biomarker for cancer immunotherapy.
Area of Science:
- Oncology
- Cancer Genomics
- Immunotherapy
Background:
- Kalirin RhoGEF kinase (KALRN) mutations are observed across various cancers, but their role in cancer pathogenesis and immunotherapy response is unclear.
- Identifying reliable biomarkers for cancer immunotherapy is critical, as only a subset of patients benefits from these treatments.
Purpose of the Study:
- To investigate the association between KALRN mutations and antitumor immunity.
- To explore the potential of KALRN mutations as biomarkers for predicting immunotherapy response.
Main Methods:
- Bioinformatic analysis of 10 cancer cohorts from The Cancer Genome Atlas (TCGA).
- In vitro and in vivo experiments to validate bioinformatics findings.
- Analysis of five cancer cohorts receiving immune checkpoint blockade therapy.
Main Results:
- KALRN-mutated cancers exhibited significantly enriched antitumor immune signatures compared to KALRN-wildtype cancers.
- KALRN mutations correlated with increased tumor mutation burden, microsatellite instability, and DNA damage repair deficiency.
- Programmed cell death 1 ligand (PD-L1) expression was upregulated in KALRN-mutated cancers, suggesting improved response to immune checkpoint blockade therapy.
- Experiments confirmed that KALRN deficiency is associated with enhanced antitumor immunity and better response to immune checkpoint inhibitors.
Conclusions:
- KALRN mutations are associated with increased antitumor immunity and may serve as a predictive biomarker for immunotherapy response in cancer patients.
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