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<p>The interaction between lymphoma cells and immune microenvironment cells and the impact of this functional interplay on therapeutic responses remain largely unexplored. Here, we utilized murine models with oncogenically active MYD88 and additional genetic lesions co-triggered at selected B cell stages to generate human-like lymphomas harboring the MYD88<sup>L265P</sup> mutation. Lymphomas exhibited behaviors ranging from clinically indolent small-cell tumors to aggressive diffuse large B-cell lymphoma (DLBCL). Genetically diverse lymphoma cells employ distinct immune evasion mechanisms that shape unique lymphoma microenvironment (LME) states. In this setting, clonally expanded T-cells function as a double-edged sword, either sustaining indolent lymphoma cell survival or promoting antitumor responses in DLBCL. Consequently, the efficacy of standard-of-care and novel immunotherapies was determined using individual T-cell features. Furthermore, the experimental targeting of newly identified immune mechanisms has improved therapeutic responses in vivo. Our results elucidate that genetically driven LME landscapes influence therapeutic outcomes across distinct lymphoma subtypes, providing proof-of-concept for personalized treatment based on immune LME information.</p>

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Genetically driven immune microenvironment states associate with therapeutic responses in MYD88 mutant lymphomas

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月20日

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  • Jon Celay,
  • Miriam Recalde,
  • Maria V. Revuelta,
  • Marta Larrayoz,
  • Carmen Vicente,
  • Teresa Lozano,
  • Carmen Gil,
  • Jennifer R. Chapman,
  • Marcos Garcia-Lacarte,
  • Carmen Gonzalez,
  • Beñat Ariceta,
  • Sara Rodriguez,
  • Marta Lasa,
  • Maria J. Garcia-Barchino,
  • Vicente Fresquet,
  • Maddalen Jimenez,
  • Sonia Sanz,
  • Ming-Qing Du,
  • Giovanna Roncador,
  • Zaira Vega,
  • Antonio Sacco,
  • Aldo Roccaro,
  • Gero Knittel,
  • Hans Christian Reinhardt,
  • Rocco Piazza,
  • Sylvia Herter,
  • Rebecca Goodhew,
  • Jonathan Caron,
  • Damien Roos-Weil,
  • Jesus San Miguel,
  • Miguel Canales,
  • Daniel J. Hodson,
  • Izidore S. Lossos,
  • Juan J. Lasarte,
  • Sergio Roa,
  • Felipe Prosper,
  • Bruno Paiva,
  • Leandro Cerchietti,
  • Jose A. Martinez-Climent

摘要

The interaction between lymphoma cells and immune microenvironment cells and the impact of this functional interplay on therapeutic responses remain largely unexplored. Here, we utilized murine models with oncogenically active MYD88 and additional genetic lesions co-triggered at selected B cell stages to generate human-like lymphomas harboring the MYD88L265P mutation. Lymphomas exhibited behaviors ranging from clinically indolent small-cell tumors to aggressive diffuse large B-cell lymphoma (DLBCL). Genetically diverse lymphoma cells employ distinct immune evasion mechanisms that shape unique lymphoma microenvironment (LME) states. In this setting, clonally expanded T-cells function as a double-edged sword, either sustaining indolent lymphoma cell survival or promoting antitumor responses in DLBCL. Consequently, the efficacy of standard-of-care and novel immunotherapies was determined using individual T-cell features. Furthermore, the experimental targeting of newly identified immune mechanisms has improved therapeutic responses in vivo. Our results elucidate that genetically driven LME landscapes influence therapeutic outcomes across distinct lymphoma subtypes, providing proof-of-concept for personalized treatment based on immune LME information.