Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer
Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)
To overcome PDAC resistance to Kras* targeting using MRTX1133 or daraxonrasib, which enhances infiltration T cells, including various CD8+ T cell, CD4+ conventional T cell, and Treg phenotypes, Mahadevan et al. found that the addition of anti-CTLA-4 (but not other ICB) synergized by further increasing TILs, reprogramming Tregs to a more naive (less suppressive) phenotype, reversing exhaustion in CD8+ T cells, and promoting the formation of TLSs, together resulting in better PDAC suppression and longer survival. Treg reprogramming occurred through epigenetic downregulation of AP-1 transcription factors in the IL-10 and IL-35 promoter regions.
Contributed by Lauren Hitchings
Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)
To overcome PDAC resistance to Kras* targeting using MRTX1133 or daraxonrasib, which enhances infiltration T cells, including various CD8+ T cell, CD4+ conventional T cell, and Treg phenotypes, Mahadevan et al. found that the addition of anti-CTLA-4 (but not other ICB) synergized by further increasing TILs, reprogramming Tregs to a more naive (less suppressive) phenotype, reversing exhaustion in CD8+ T cells, and promoting the formation of TLSs, together resulting in better PDAC suppression and longer survival. Treg reprogramming occurred through epigenetic downregulation of AP-1 transcription factors in the IL-10 and IL-35 promoter regions.
Contributed by Lauren Hitchings
ABSTRACT: 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.
Author Info:
(1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (2) 3P-Medicine Laboratory, Medical University of Gdansk, 80-210 Gdansk, Poland (3
) Departments of Anatomical Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (4) Department of Investigative Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA (5) Institute for Applied Science and TRACTION platform, University of Texas MD Anderson Cancer Center, Houston, TX, USA (6) Department of Bioengineering, Rice University, Houston, TX, USA (7) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA (8) Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
