Soluble CD155 immune complexes reprogram DNAM-1 signaling to potentiate antitumor immunity

Kinoshita, S.; Matsuo, T.; Takeuchi, N.; Okumura, G.; Ide, N.; Iguchi-Manaka, A.; Gwon, S.; Sugiyama, E.; Koyama, S.; Tahara, H.; Nakahashi-Oda, C.; Shibuya, A.; Shibuya, K.

doi:10.64898/2026.05.16.725599

bioRxiv · 10.64898/2026.05.16.725599

Soluble CD155 immune complexes reprogram DNAM-1 signaling to potentiate antitumor immunity

Kinoshita, S.·Matsuo, T.·Takeuchi, N.·Okumura, G.·Ide, N.·Iguchi-Manaka, A.·Gwon, S.·Sugiyama, E.·Koyama, S.·Tahara, H.·Nakahashi-Oda, C.·Shibuya, A.·Shibuya, K.

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Abstract

Resistance to immune checkpoint inhibitors (ICIs) remains a major challenge in oncology, yet the mechanisms that selectively disable activating pathways are poorly defined. Here, we identify tumor-derived soluble CD155 (sCD155) as a systemic checkpoint that rewires DNAM-1 signaling to drive immunotherapy resistance. High plasma sCD155 levels correlate with impaired anti-PD-1 responses in patients with non-small cell lung cancer. Mechanistically, sCD155 selectively suppresses DNAM-1-dependent activation of CD8+ T and NK cells, uncoupling ICIs from cytotoxic function. Intriguingly, a selective anti-sCD155 monoclonal antibody does not neutralize the ligand, but rather converts it into an activating scaffold. This complex induces Fc{gamma}R-anchored DNAM-1 microcluster formation and robust downstream signaling, effectively switching the checkpoint into a co-stimulatory signal. This reprogramming restores CTL function, suppresses metastasis, and augments PD-1/TIGIT blockade to achieve durable immunity. Our findings establish antibody-mediated receptor architecture rewiring as a therapeutic principle to overcome cancer immune resistance.

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Kinoshita, S., Matsuo, T., Takeuchi, N., Okumura, G., Ide, N., Iguchi-Manaka, A., Gwon, S., Sugiyama, E., Koyama, S., Tahara, H., Nakahashi-Oda, C., Shibuya, A., Shibuya, K.. 2026-05-19. Soluble CD155 immune complexes reprogram DNAM-1 signaling to potentiate antitumor immunity. https://doi.org/10.64898/2026.05.16.725599

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