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ORIGINAL RESEARCH article

Front. Immunol.
Sec. T Cell Biology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1444424

Dissociation of LAG-3 inhibitory cluster from TCR microcluster by immune checkpoint blockade

Provisionally accepted
Akiko Hashimoto-Tane Akiko Hashimoto-Tane 1,2Edward P. Bowman Edward P. Bowman 3Machie Sakuma Machie Sakuma 1Natsumi Yoneda Natsumi Yoneda 1Katsuyuki Yugi Katsuyuki Yugi 1Rene De Waal Malefyt Rene De Waal Malefyt 3Takashi Saito Takashi Saito 1*
  • 1 RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, Japan
  • 2 MSD Japan, Tokyo, Tokyo, Japan
  • 3 Merck & Co., Inc., Kenilworth, New Jersey, United States

The final, formatted version of the article will be published soon.

    Lymphocyte activation gene (Lag)-3 is an inhibitory co-receptor and target of immune checkpoint inhibitor (ICI) therapy for cancer. The dynamic behavior of Lag-3 was analyzed at the immune synapse upon T cell activation to elucidate Lag-3 inhibitory mechanism. Lag-3 formed clusters and co-localized with TCR-microcluster (MC) upon T cell activation similar to PD-1. Lag-3 blocking antibodies (Ab) inhibited the co-localization between Lag-3 and TCR-MC without inhibiting Lag-3 cluster formation.Lag-3 also inhibited MHC-II-independent stimulation and Lag-3 Ab which did not block MHC-II binding yet could still block Lag-3's inhibitory function suggesting that the Lag-3 Ab blocks the Lag-3 inhibitory signal by dissociating the co-assembly of TCR-MC and Lag-3 clusters. Consistent with the combination benefit of PD-1 and Lag-3 Abs to augment T cell responses, bispecific Lag-3/PD-1 antagonists effectively inhibited both cluster formation and co-localization of PD-1 and Lag-3 with TCR-MC. Therefore, Lag-3 inhibits T cell activation at TCR-MC and the target of Lag-3 ICI is to dissociate the co-localization Lag-3 with TCR-MC.

    Keywords: LAG-3, T cell activation, Immune checkpoint blockade, TCR microcluster, PD-1, inhibitory co-receptor

    Received: 05 Jun 2024; Accepted: 24 Jul 2024.

    Copyright: © 2024 Hashimoto-Tane, Bowman, Sakuma, Yoneda, Yugi, De Waal Malefyt and Saito. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Takashi Saito, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, 230-0045, Kanagawa, Japan

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