Related Experiment Video

Updated: Jun 13, 2025

Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
07:55

Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer

Published on: January 17, 2025

682

Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint

Dig B Mahat1, Heena Kumra2, Sarah A Castro1

  • 1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Biorxiv : the Preprint Server for Biology
|September 11, 2024
PubMed

Insights

A common pancreatic cancer mutation (p53R172H) creates an immunosuppressive tumor microenvironment, hindering cancer treatments. This occurs by increasing Cxcl1 chemokine expression, which promotes tumor growth and reduces immune checkpoint inhibitor efficacy.

Area of Science:

  • Oncology
  • Cancer Immunology
  • Molecular Biology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options.
  • Activating KRAS mutations and p53 alterations are common in PDAC.
  • The impact of these mutations on the tumor microenvironment (TME) and immune response is not fully understood.

Purpose of the Study:

  • To investigate how the p53R172H mutation influences the tumor microenvironment (TME) in pancreatic cancer.
  • To determine the mechanisms by which p53R172H affects tumor growth and response to immune checkpoint inhibitors (ICIs).

Main Methods:

  • Analysis of p53R172H effects on the TME and ICI efficacy in PDAC models.
  • Investigation of Cxcl1 chemokine upregulation as a mediator of p53R172H functions.
  • Mechanistic studies on p53R172H interaction with Cxcl1 gene enhancers, involving the NF-κB pathway.

Main Results:

  • The p53R172H mutation establishes an immunosuppressive TME, promoting tumor growth.
  • p53R172H diminishes the effectiveness of immune checkpoint inhibitors (ICIs).
  • Upregulation of the immunosuppressive chemokine Cxcl1 mediates these pro-tumorigenic effects, driven by p53R172H binding to Cxcl1 enhancers in an NF-κB-dependent manner.

Conclusions:

  • The p53R172H mutation hijacks enhancer activity to increase Cxcl1 expression.
  • This leads to an immunosuppressive TME that impairs ICI efficacy in PDAC.
  • Targeting this mechanism could offer new therapeutic strategies for pancreatic cancer.
Keywords:
Cxcl1PDACchemokineeRNAenhancerimmune checkpoint inhibitorsimmunosuppressionimmunotherapymutant p53p53R172Hp53R175H

More Related Videos

Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma06:21

Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma

Published on: November 19, 2019

11.1K
Yeast As a Chassis for Developing Functional Assays to Study Human P5314:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

9.5K

Related Concept Videos

Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.5K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.2K
The Tumor Microenvironment02:17

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
6.6K
Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
491
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K