We are excited to share with you work by Sarah Staudt et al., entitled “Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk”. It is the first manuscript of our young Luu lab established at the Universitätsklinikum Würzburg and Julius-Maximilians-Universität Würzburg, available as preprint on Bioxriv for the community.
Emerging data have highlighted a correlation between microbiome composition and cancer immunotherapy outcome. While commensal bacteria and their metabolites are known to modulate the host environment, contradictory effects and a lack of mechanistic understanding impede the translation of microbiome-based therapies into the clinic.
In this study, we demonstrate that abundance of the commensal metabolite pentanoate is predictive of chimeric antigen receptor (CAR) T cell patient survival. Its implementation in the CAR T cell manufacturing workflow enables the engineered T cells to overcome hostile tumor microenvironments (TMEs) by hijacking epigenetic-metabolic crosstalks.
Key findings:
• Abundance of the commensal metabolite pentanoate in patient stool is predictive of CAR T cell outcome in the clinic
• Pentanoate is a unique modulator capable of hijacking cellular metabolism via feeding into the TCA cycle through two different entry points to facilitate epigenetic reprogramming at the histone level
• Pentanoate-engineered CAR T cells benefit from metabolic-epigenetic reprogramming to acquire TME resistance, superior anti-tumor function, and cell persistence
• Clinically relevant drugs are not capable of fully recapitulating the effects of pentanoate treatment
• Single cell-RNA sequencing of tumor-infiltrating lymphocytes identified a naive-like T cell state and a reduction in T cell exhaustion in the immunosuppressive TME in vivo.
We are very proud of this collaborative effort bringing together experts and pioneers from the fields of microbiome and clinical research, immunometabolism, protein biochemistry and cancer genomics to elucidate novel mechanisms and advance the engineering of CAR T cells in a rational, interdisciplinary manner. I have always imagined that science is most fun when you do it with the T2EVOLVE family, great partners and friends. Thanks to all co-authors for their contributions and helping us to get to this stage! We think that the results could be of interest for a broad readership with basic, translational, and clinical background.
So: Read, share, discuss! 😊
The EBMT European School of Haematology (ESH)
#t2evolve #CARTcells #cancerresearch #immunology #immunotherapy #microbiome
