APR 20, 2022 7:00 AM PDT

A Specialized Mouse Model Identifies Genetic Regulators of Immunotherapy Response

WRITTEN BY: Katie Kokolus

Recent advances in immune checkpoint inhibitors (ICI) have led to significant clinical benefits for patients with various hard-to-treat cancers. However, many patients remain resistant to these benefits. This has motivated scientists to develop methods to increase the efficacy of ICIs and uncover new ways to regulate ICI responsiveness to the forefront of cancer research.  

While tumors elicit survival mechanisms involved in ICI resistance, the role of genetic background in regulating therapeutic outcomes remains unknown. To investigate a potential role of genetic makeup in ICI response, a team of researchers from the Barbara Ann Karmanos Cancer Institute at Wayne State University has utilized a unique genetically diverse mouse model. The researchers generated Diversity Outbred (DO) and Collaborative Cross (CC) mice for their study published today in OncoImmunology.  

DO and CC mice present unique models that closely mirror human populations. Compared to traditional mouse models, which have a similar genetic makeup from animal to animal, DO mice provide genetic variation resulting in a range of responses to ICIs, similar to what is observed in a clinical setting. CC mice, generated from DO strains, provide an added experimental benefit as the investigators can use them to replicate specific phenotypes of ICI responders and non-responders.  The researchers used F1 crosses in their study, meaning that each mouse could be given the exact same tumor.  However, since these mice have notable genetic diversity, researchers can use them to pinpoint specific regions of the normal genome associated with positive or negative therapeutic responses. 

Using a murine melanoma tumor, B16F0, the study found that the host’s genetic background regulated ICI response. Specifically, one genetic region on chromosome 13 played a significant role in ICI responsiveness. Chromosome 13 contains genes coding for murine prolactin, a hormone related to milk production after giving birth, which also has a lesser-known function as an immune signaling protein. The study identified host-driven prolactin as a specific regulator of therapeutic ICI response.

The study included a comprehensive quantification of cytotoxic T lymphocytes (CTLs), the immune cells responsible for killing cancer cells. Notably, CTL infiltration is a readout that can be used as a biomarker to predict ICI response. The authors used ImageJ plugin Weka segmentation technology to quantitate these components on whole slide scans following immunohistochemistry staining. Labroots spoke with lead author Justin Hackett, MD/PhD Candidate, who told us, “It’s a powerful tool that gives us great insight into the infiltration status of a tumor without having to only pick high power fields.” Their analysis revealed that responder strains show high levels of CTL infiltration following treatment. 

Senior author Heather Gibson, PhD, Assistant Professor of Oncology, also spoke to Labroots about the future directions of this project. Gibson noted, “We are now in a position to find the causal genes within these loci of interest and determine the mechanism(s) for how they influence treatment response. We also want to test whether these genes/pathways translate to human immune cells in the context of immune checkpoint inhibitors. Ultimately, this might lead us to improved biomarkers or new co-therapeutics to improve response rates.”

Hackett was enthusiastic about his study's impact on other biomedical research programs.  He stated, “I would love for the work we’ve done be taken on by others to use the CC models for immunotherapy research.  Our work shows that you can consistently model different levels of responses to the same tumor.  This opens us avenues to explore what changes an identical tumor undergoes with immune pressure or explore the differences between immunophenotypes to the same tumor challenge.”  Gibson added, “This is the first time these animal models have been used for cancer immunotherapy.  They have a lot of potential for discovering resistance pathways, testing new therapeutics, and furthering our understanding of the host immune response cross-talk with tumor.”

 

Sources: OncoImmunology, Br J Cancer

About the Author
PhD
PhD in Tumor Immunology. I am interested in developing novel strategies to improve the efficacy of immunotherapies used to extend cancer survivorship.
You May Also Like
FEB 08, 2022
Health & Medicine
More Younger Adults Diagnosed with Advanced Colorectal Cancer
FEB 08, 2022
More Younger Adults Diagnosed with Advanced Colorectal Cancer
According to the American Cancer Society, early-onset colorectal cancer has been on the rise for the past 30 to 50 years ...
MAR 08, 2022
Technology
Black Prostate Cancer Patients Are Less Likely to Receive Diagnostic MRIs. Why?
MAR 08, 2022
Black Prostate Cancer Patients Are Less Likely to Receive Diagnostic MRIs. Why?
Prostate cancer affects an estimated 1 in 8 men, with over 250,000 new cases diagnosed each year. More specifically, pro ...
APR 11, 2022
Cancer
What is a Cancer Center?
APR 11, 2022
What is a Cancer Center?
Over 50 years ago, President Richard Nixon signed the National Cancer Act of 1971, a landmark piece of legislation ...
APR 19, 2022
Health & Medicine
Microplastics Found in Human Lungs. Are They Dangerous?
APR 19, 2022
Microplastics Found in Human Lungs. Are They Dangerous?
Research out of Hull York Medical School in England found small plastic debris known as microplastics deep in the lungs ...
MAY 10, 2022
Cardiology
Screen Time is Linked to Heart Disease and Cancer
MAY 10, 2022
Screen Time is Linked to Heart Disease and Cancer
Spending too much time in front of the TV or computer can lead to major health risks.
JUN 06, 2022
Immunology
Using Antibodies to Create Potent Cancer Treatments
JUN 06, 2022
Using Antibodies to Create Potent Cancer Treatments
Cancer can arise from a variety of aberrations that cause cells to divide uncontrollably, and form a tumor. The causes o ...
Loading Comments...