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<p>Heterogeneity in antigen expression on cancer cells limits clinical benefit of engineered T-cell therapies and underpins treatment resistance through antigen escape. Here, we present a strategy to improve recognition and lysis of tumors with suboptimal antigen expression through a separate engineered receptor that selectively boosts cytotoxic signaling and immune synapse formation. This synapse-stabilizing receptor (SSR) harbors a modified linker for activation of T cells (LAT) endodomain that amplifies CD3ζ signaling upon binding to a secondary tumor antigen resulting in an augmented Ca2+ flux, activation of MAPK and NF-kB signaling, maturation of immune synapse, and enhanced T-cell degranulation. Removing C-terminal amino acids 178-233 in the LAT endodomain (LAT177) was necessary to minimize SSR-mediated cytotoxicity. In models of acute myeloid leukemia, we show that a CD38-targeting SSR boosts cytolysis of antigen-low cancer cells via a C-type lectin-like molecule-1 (CLL1)-specific chimeric antigen receptor (CAR) and a survivin-specific T cell receptor (TCR). Unlike another CAR, SSR does not produce significant cytotoxicity against normal CD38+ tissues. Our study thus shows that SSR arming enhances targeting of antigenically heterogeneous cancers without compromising safety and selectivity of therapeutic T cells.</p>

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Enhancing CAR- and TCR-mediated targeting of cancer via an immune synapse-stabilizing receptor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月4日

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  • Chiou-Tsun Tsai,
  • Jorge Ibanez-Vega,
  • Pan Yin,
  • Robert Teis,
  • Norihiro Watanabe,
  • Tadahiro Honda,
  • Mikhail Valkov,
  • Peter J. Chockley,
  • Lourdes Asenath Jimenez Madrigal,
  • Giedre Krenciute,
  • Maksim Mamonkin

摘要

Heterogeneity in antigen expression on cancer cells limits clinical benefit of engineered T-cell therapies and underpins treatment resistance through antigen escape. Here, we present a strategy to improve recognition and lysis of tumors with suboptimal antigen expression through a separate engineered receptor that selectively boosts cytotoxic signaling and immune synapse formation. This synapse-stabilizing receptor (SSR) harbors a modified linker for activation of T cells (LAT) endodomain that amplifies CD3ζ signaling upon binding to a secondary tumor antigen resulting in an augmented Ca2+ flux, activation of MAPK and NF-kB signaling, maturation of immune synapse, and enhanced T-cell degranulation. Removing C-terminal amino acids 178-233 in the LAT endodomain (LAT177) was necessary to minimize SSR-mediated cytotoxicity. In models of acute myeloid leukemia, we show that a CD38-targeting SSR boosts cytolysis of antigen-low cancer cells via a C-type lectin-like molecule-1 (CLL1)-specific chimeric antigen receptor (CAR) and a survivin-specific T cell receptor (TCR). Unlike another CAR, SSR does not produce significant cytotoxicity against normal CD38+ tissues. Our study thus shows that SSR arming enhances targeting of antigenically heterogeneous cancers without compromising safety and selectivity of therapeutic T cells.