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Updated: Jun 10, 2025
Testing Cancer Immunotherapeutics in a Humanized Mouse Model Bearing Human Tumors
Published on: December 16, 2022
CD94 deficiency or blockade unleashes the anti-tumor immunity in mice and humanized murine models
Jiarui Li1, Xianwei Wang1, Guoshuai Cao2
1Key Laboratory of Immune Response and Immunotherapy, The Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China.
Abstract:
NKG2 family members have emerged as promising targets in tumor immunotherapy. CD94 can dimerize with both inhibitory and activating NKG2 proteins, while the overall effect and value of targeting CD94 on anti-tumor immunity are unclear. Here, it is shown that the expression of CD94 is upregulated on tumor-infiltrating natural killer (NK) cells and CD8+ T cells, and is related to their exhausted characteristics. Tumor-bearing CD94 knockout (CD94-KO) mice exhibit delayed tumor growth, decreased lung metastases, and prolonged survival. Single cell RNA-seq reveals a remodeled tumor microenvironment in CD94-KO mice, with a reduction in immunosuppressive cells and an increase in anti-tumor immune cells. Moreover, NK cells and CD8+ T cells become proliferative and strongly tumoricidal in CD94-KO mice, thus contributing to the tumor inhibition effect of CD94 deficiency. Treatment with a humanized anti-CD94 blocking antibody (h15C10) alone, in tumor-bearing humanized mouse, delays tumor progression, and improves the therapeutic efficacy of PD-L1 blockade through combination therapy. Our study indicates that CD94 may work as a candidate target in checkpoint immunotherapy.
Insights
Targeting CD94, a protein found on immune cells, shows promise in cancer immunotherapy. Blocking CD94 in mice delayed tumor growth and improved survival, suggesting its potential as a therapeutic target.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Medicine
Background:
- NKG2 family members are key targets in tumor immunotherapy.
- CD94 dimerizes with NKG2 proteins, but its role in anti-tumor immunity is not fully understood.
Purpose of the Study:
- To investigate the role of CD94 in anti-tumor immunity.
- To evaluate CD94 as a potential therapeutic target in cancer immunotherapy.
Main Methods:
- Utilized CD94 knockout (CD94-KO) mouse models.
- Performed single-cell RNA sequencing (scRNA-seq) to analyze the tumor microenvironment.
- Tested a humanized anti-CD94 blocking antibody (h15C10) in humanized mice.
Main Results:
- CD94 expression is upregulated on tumor-infiltrating natural killer (NK) and CD8+ T cells, correlating with immune exhaustion.
- CD94-KO mice demonstrated delayed tumor growth, reduced lung metastasis, and increased survival.
- scRNA-seq revealed a shift in the tumor microenvironment towards reduced immunosuppression and enhanced anti-tumor immunity in CD94-KO mice.
- NK and CD8+ T cells exhibited increased proliferation and tumoricidal activity in CD94-KO mice.
- Anti-CD94 antibody treatment delayed tumor progression and enhanced the efficacy of PD-L1 blockade in combination therapy.
Conclusions:
- CD94 plays a significant role in regulating anti-tumor immunity.
- CD94 deficiency promotes a more effective anti-tumor immune response.
- CD94 is a potential candidate target for checkpoint immunotherapy.
