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<p>BH3 mimetics are apoptogenic but rarely cause immunogenic cell death (ICD), limiting durable antitumor immunity. We hypothesized that an ICD-inducing immunoadjuvant could convert BH3-mimetic-triggered tolerogenic apoptosis into immunogenic priming, enhancing checkpoint immunotherapy and overcoming immune evasion in AML. We in vivo evaluated the hydroxycoumarin OT-55, combined with the Bcl-xL inhibitor A-1331852, to enhance PD-1/Tim-3 blockade in Bcl-xL-dependent murine prophylactic and bilateral AML vaccination models. To define the clinical and immunological context, we derived a nine-gene AML ICD score (<i>ATG5, CALR, CD8A, CD8B, IFNGR1, IL1B, PDIA3, PIK3CA, TLR4</i>) by screening 34 ICD-associated genes in transcriptomes of three AML patient cohorts (TARGET-AML, BEAT-AML, GSE37642), retaining genes consistently associated with favorable prognosis (HR &lt; 1, Cox regression). These cohorts were dichotomized by median ICD score to infer immune composition (CIBERSORTx) and profile driver mutations, and to assess blast maturation. High ICD scores were associated with an immune-activated state, increased CD8⁺ T cells, activated dendritic cells, and higher <i>HAVCR2</i> (Tim-3) expression, consistent with a survival advantage. Bone marrow scRNA-seq from AML and healthy donors revealed ICD-related and progenitor-to-intermediate exhausted T cells, alongside T cell depletion in myelomonocytic AML. Experimentally, we used murine C1498 myelomonocytic AML cells to evaluate OT-55 combined with A-1331852 by prophylactic whole-cell vaccination for DAMP release, dependency testing (CRT neutralization and apyrase), antigen-specific CD8⁺ responses, and synergy with anti-PD-1/anti-Tim-3 therapy in a bilateral tumor model, while monitoring hematologic and serum parameters. OT-55 reduced C1498 viability, induced CRT exposure and ATP release, and conferred CRT/ATP-dependent, but HMGB1-independent, vaccine protection. While A-1331852 was cytotoxic yet weakly immunogenic, its combination with OT-55 enhanced DAMP release, increased CD8⁺ effector functions, and, with PD-1/Tim-3 blockade, achieved local and distant tumor control with low toxicity. These findings identify OT-55 as an immunogenic adjuvant converting tolerogenic BH3 mimetic-driven apoptosis into ICD, providing a proof-of-concept immunogenic treatment for myelomonocytic AML.</p>

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OT-55 reshapes tolerogenic BH3-mimetic-induced apoptosis toward immunogenic cell death in acute myeloid leukemia, potentiating PD-1/Tim-3 blockade

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • Yejin Lee,
  • Eun-Ji Kwon,
  • Sruthi Reddy Gajulapalli,
  • Ji Yeon Paik,
  • Barbora Orlikova-Boyer,
  • Artur M. S. Silva,
  • Hyuk-Jin Cha,
  • Claudia Cerella,
  • Marc Diederich

摘要

BH3 mimetics are apoptogenic but rarely cause immunogenic cell death (ICD), limiting durable antitumor immunity. We hypothesized that an ICD-inducing immunoadjuvant could convert BH3-mimetic-triggered tolerogenic apoptosis into immunogenic priming, enhancing checkpoint immunotherapy and overcoming immune evasion in AML. We in vivo evaluated the hydroxycoumarin OT-55, combined with the Bcl-xL inhibitor A-1331852, to enhance PD-1/Tim-3 blockade in Bcl-xL-dependent murine prophylactic and bilateral AML vaccination models. To define the clinical and immunological context, we derived a nine-gene AML ICD score (ATG5, CALR, CD8A, CD8B, IFNGR1, IL1B, PDIA3, PIK3CA, TLR4) by screening 34 ICD-associated genes in transcriptomes of three AML patient cohorts (TARGET-AML, BEAT-AML, GSE37642), retaining genes consistently associated with favorable prognosis (HR < 1, Cox regression). These cohorts were dichotomized by median ICD score to infer immune composition (CIBERSORTx) and profile driver mutations, and to assess blast maturation. High ICD scores were associated with an immune-activated state, increased CD8⁺ T cells, activated dendritic cells, and higher HAVCR2 (Tim-3) expression, consistent with a survival advantage. Bone marrow scRNA-seq from AML and healthy donors revealed ICD-related and progenitor-to-intermediate exhausted T cells, alongside T cell depletion in myelomonocytic AML. Experimentally, we used murine C1498 myelomonocytic AML cells to evaluate OT-55 combined with A-1331852 by prophylactic whole-cell vaccination for DAMP release, dependency testing (CRT neutralization and apyrase), antigen-specific CD8⁺ responses, and synergy with anti-PD-1/anti-Tim-3 therapy in a bilateral tumor model, while monitoring hematologic and serum parameters. OT-55 reduced C1498 viability, induced CRT exposure and ATP release, and conferred CRT/ATP-dependent, but HMGB1-independent, vaccine protection. While A-1331852 was cytotoxic yet weakly immunogenic, its combination with OT-55 enhanced DAMP release, increased CD8⁺ effector functions, and, with PD-1/Tim-3 blockade, achieved local and distant tumor control with low toxicity. These findings identify OT-55 as an immunogenic adjuvant converting tolerogenic BH3 mimetic-driven apoptosis into ICD, providing a proof-of-concept immunogenic treatment for myelomonocytic AML.