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Peer-reviewedCC BY-NC 4.0Immune Network

PD-L1-Directed CD226 Agonism Enhances Antitumor Activity by Amplifying T Cell Responses to Limiting Stimulation

  • Yunju Jo1,2
  • Hyejin Ahn3
  • Hye-Bin Kim3
  • Gaeun Song1,2
  • Hye-In Sim1,2
  • Kiyeon Park3
  • Taehyeong Kim3
  • Haeun Son3
  • Hyun Kyu Song2,4
  • Hyung-seung Jin3
  • Yoon Park1,5
5 affiliations
  1. 1Chemical and Biological Integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea .
  2. 2Department of Life Sciences, Korea University, Seoul 02481, Korea .
  3. 3Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea .
  4. 4National Research Laboratory for Convergence Degradation Biology, Korea University, Seoul 02481, Korea .
  5. 5Division of Biomedical Science and Technology, Korea Institute of Science and Technology (KIST) School, University of Science and Technology (UST), Seoul 02792, Korea .
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Abstract

Immune checkpoint blockade restores antitumor T cell responses, but efficacy can be limited by insufficient costimulation. Here, we investigated CD226 agonism and generated a CD226×PD-L1 bispecific Ab combining CD226 costimulation with PD-L1 blockade. CD226 agonism enhanced responses to limiting TCR stimulation and IL-2-driven responses in the absence of concurrent TCR stimulation. The bispecific Ab elicited stronger CD4+ and CD8+ T cell responses than either Ab alone or the combination. Conditioning CD226 agonism on target cell PD-L1 engagement produced greater T cell and NK cell cytotoxicity than the combination, particularly under effector-limited conditions and repeated target challenges. It also improved tumor control in adoptive-transfer models using antigen-specific TCR-T cells and remained effective with preactivated T cells despite the absence of continued cognate antigen stimulation. These findings identify PD-L1-directed CD226 agonism as a potential immunotherapeutic strategy that exploits the signal-amplifying properties of CD226 to reinforce antitumor lymphocyte responses under limiting stimulation.

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Cite

BibTeXRIS
BibTeX
@article{jo2026pdl1directed,
  title = {{PD-L1-Directed CD226 Agonism Enhances Antitumor Activity by Amplifying T Cell Responses to Limiting Stimulation}},
  author = {Yunju Jo and Hyejin Ahn and Hye-Bin Kim and Gaeun Song and Hye-In Sim and Kiyeon Park and Taehyeong Kim and Haeun Son and Hyun Kyu Song and Hyung-seung Jin and Yoon Park},
  journal = {Immune Network},
  year = {2026},
  month = oct,
  doi = {10.4110/in.2026.26.e46},
  url = {https://doi.org/10.4110/in.2026.26.e46},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - PD-L1-Directed CD226 Agonism Enhances Antitumor Activity by Amplifying T Cell Responses to Limiting Stimulation
AU  - Yunju Jo
AU  - Hyejin Ahn
AU  - Hye-Bin Kim
AU  - Gaeun Song
AU  - Hye-In Sim
AU  - Kiyeon Park
AU  - Taehyeong Kim
AU  - Haeun Son
AU  - Hyun Kyu Song
AU  - Hyung-seung Jin
AU  - Yoon Park
PY  - 2026
DA  - 2026/10/16
JO  - Immune Network
DO  - 10.4110/in.2026.26.e46
UR  - https://doi.org/10.4110/in.2026.26.e46
AB  - Immune checkpoint blockade restores antitumor T cell responses, but efficacy can be limited by insufficient costimulation. Here, we investigated CD226 agonism and generated a CD226×PD-L1 bispecific Ab combining CD226 costimulation with PD-L1 blockade. CD226 agonism enhanced responses to limiting TCR stimulation and IL-2-driven responses in the absence of concurrent TCR stimulation. The bispecific Ab elicited stronger CD4+ and CD8+ T cell responses than either Ab alone or the combination. Conditioning CD226 agonism on target cell PD-L1 engagement produced greater T cell and NK cell cytotoxicity than the combination, particularly under effector-limited conditions and repeated target challenges. It also improved tumor control in adoptive-transfer models using antigen-specific TCR-T cells and remained effective with preactivated T cells despite the absence of continued cognate antigen stimulation. These findings identify PD-L1-directed CD226 agonism as a potential immunotherapeutic strategy that exploits the signal-amplifying properties of CD226 to reinforce antitumor lymphocyte responses under limiting stimulation.
SN  - 1598-2629
SN  - 2092-6685
ER  -