
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.28.609802
preprint
1
Article
Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer
Mahat Dig B. http://orcid.org/0000-0001-7967-2851

Kumra Heena
Castro Sarah A.
Metcalf Emily
Nguyen Kim
Morisue Ryo
Ho William W.
Chen Ivy
Sullivan Brandon
Yim Leon K.
Singh Arundeep
Fu Jiayu
Waterton Sean K.
Cheng Yu-Chi
Roberge Sylvie
Moiso Enrico
Chauhan Vikash P.
Silva Hernandez Moura
Spranger Stefani http://orcid.org/0000-0003-3257-4546

Jain Rakesh K.
Sharp Phillip A.
30 8 2024
2024.08.28.609802https://creativecommons.org/licenses/by-nd/4.0/ This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.08.28.609802
nihpp-2024.08.28.609802.pdf
Summary

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we show that p53 R172H establishes an immunosuppressive TME, diminishes the efficacy of immune checkpoint inhibitors (ICIs), and enhances tumor growth. Our findings reveal that the upregulation of the immunosuppressive chemokine Cxcl1 mediates these pro-tumorigenic functions of p53 R172H . Mechanistically, we show that p53 R172H associates with the distal enhancers of the Cxcl1 gene, increasing enhancer activity and Cxcl1 expression. p53 R172H occupies these enhancers in an NF-κB-pathway-dependent manner, suggesting NF-κB’s role in recruiting p53 R172H to the Cxcl1 enhancers. Our work uncovers how a common mutation in a tumor-suppressor transcription factor appropriates enhancers, stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC.
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