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KPNA2 Drives Immunosuppression in Ovarian Cancer via CCL2/CCR2-Dependent MDSC Recruitment
Qingli Li1, Jitong Zhao2, Lu Yang1
1Cancer Center, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
Abstract:
Immunosuppression in ovarian cancer is primarily driven by myeloid-derived suppressor cells (MDSCs). This study identifies karyopherin α2 (KPNA2) as a novel regulator of this immunosuppressive process through the NF-κB/CCL2/CCR2 axis. Elevated KPNA2 expression correlates with increased intratumoral MDSC accumulation and impaired CD8+ T-cell function. Mechanistically, KPNA2 directly binds to and facilitates nuclear translocation of NF-κB/p65, thereby driving CCL2 transcription, while also exhibiting an auxiliary, p65-independent function in CCL2 induction. Secreted CCL2 recruits MDSCs in a CCR2-dependent manner, establishing a potent immunosuppressive tumor microenvironment. Therapeutic targeting via MDSC depletion, pharmacological CCR2 blockade, or direct KPNA2 knockdown effectively inhibited metastasis, enhanced CD8+ T-cell infiltration, and suppressed tumor growth. Importantly, CCR2 inhibition synergized with anti-PD-L1 therapy, revealing a promising combination immunotherapeutic strategy for KPNA2-high ovarian cancer. These findings establish the KPNA2-governed NF-κB/CCL2/CCR2 pathway as a central mechanism of immune evasion and a viable target for combination immunotherapy in ovarian cancer.
Insights
Karyopherin alpha 2 (KPNA2) drives immunosuppression in ovarian cancer by promoting myeloid-derived suppressor cells (MDSCs) via the NF-κB/CCL2/CCR2 pathway. Targeting KPNA2 or CCR2 offers a promising strategy for ovarian cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Ovarian cancer immunosuppression is largely mediated by myeloid-derived suppressor cells (MDSCs).
- Identifying novel regulators of MDSC function is crucial for developing effective ovarian cancer therapies.
Purpose of the Study:
- To identify novel regulators of immunosuppression in ovarian cancer.
- To elucidate the role of karyopherin alpha 2 (KPNA2) in regulating the tumor microenvironment and immune evasion.
Main Methods:
- Analysis of KPNA2 expression in ovarian tumors.
- Investigation of KPNA2's interaction with NF-κB/p65.
- Assessment of CCL2 transcription and secretion.
- Evaluation of MDSC recruitment via the CCR2 axis.
- Testing therapeutic interventions including MDSC depletion, CCR2 blockade, KPNA2 knockdown, and anti-PD-L1 therapy.
Main Results:
- Elevated KPNA2 expression correlates with increased intratumoral MDSCs and impaired CD8+ T-cell function.
- KPNA2 facilitates NF-κB/p65 nuclear translocation, driving CCL2 transcription and MDSC recruitment.
- Therapeutic targeting of KPNA2, CCR2, or MDSCs suppressed tumor growth and metastasis.
- CCR2 inhibition synergized with anti-PD-L1 therapy in KPNA2-high ovarian cancer.
Conclusions:
- The KPNA2-governed NF-κB/CCL2/CCR2 pathway is a key mechanism of immune evasion in ovarian cancer.
- Targeting this pathway, particularly KPNA2 and CCR2, represents a viable therapeutic strategy.
- Combination immunotherapy involving CCR2 inhibition and anti-PD-L1 holds promise for treating KPNA2-high ovarian cancer.
