Scholarlink

<p>Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8<sup>+</sup> T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月27日

查看全文
  • Krishnan K. Mahadevan,
  • Ana S. Maldonado,
  • Bingrui Li,
  • Aaron A. Bickert,
  • Adrian Kacperczyk-Perdyan,
  • Shreyasee V. Kumbhar,
  • Sujan Piya,
  • Amari M. Sockwell,
  • Sami J. Morse,
  • Kent Arian,
  • Hikaru Sugimoto,
  • Shabnam Shalapour,
  • David S. Hong,
  • Timothy P. Heffernan,
  • Anirban Maitra,
  • Raghu Kalluri

摘要

Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications.