MD Anderson Research Highlights for November 3, 2021

HOUSTON ― The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recently published studies in basic, translational and clinical cancer research from MD Anderson experts. Current advances include the cost-effectiveness of expanded lung cancer screening criteria, a novel biomarker for predicting immunotherapy responses, development of a technique for multiplex single-cell chromatin profiling, combination immunotherapy for bone metastatic prostate cancer, understanding drivers of lung cancer metastasis, and enabling new T cell therapies for treating COVID-19.

Expansion of lung cancer screening criteria found to be cost-effective

In March 2021, the U.S. Preventive Services Task Force (USPSTF) issued a new recommendation for lung cancer screening that nearly doubled the number of people eligible for screening by lowering the minimum age and years of smoking history required. A study led by Iakovos Toumazis, Ph.D., and the Cancer Intervention and Surveillance Modeling Network (CISNET) Lung Working Group found the 2021 USPSTF recommendation was cost-effective compared to the 2013 recommendation it replaced. The team used a comparative modeling approach to determine if the expected increased costs of screening justified the expected health gains. The 2021 recommendation was cost-effective according to a threshold of $100,000 per quality-adjusted life-year added. Other strategies that expand the screening criteria further by including individuals who quit smoking longer than 15 years were found to be even more cost-effective. Learn more in JAMA Oncology.

Gene signature predicts immunotherapy response in cancers with low mutation rates

Immune checkpoint blockade (ICB) offers durable responses for many, but not all, patients with cancer. A high tumor mutation burden (TMB) can predict responses in a subset of cancer types, but it is not reliable as a universal biomarker. A new study led by Daniel McGrail, Ph.D., and Shiaw-Yih Lin, Ph.D., discovered a novel biomarker associated with ICB response in cancers without a high TMB. A gene expression signature indicating defects in replication stress response (RSR), a type of DNA damage response pathway, accurately predicted responses in 12 independent patient cohorts across seven different tumor types. The researchers demonstrated that regulating RSR activity could change ICB responses in preclinical models of breast and kidney cancer, and RSR defects led to an accumulation of immune-stimulating single-stranded DNA. In addition to identifying a new biomarker, these findings suggest that inducing RSR defects may be useful to improve ICB responses in certain patients. Learn more in Science Translational Medicine.

New technique allows single-cell chromatin profiling on multiple samples simultaneously

DNA is packaged with proteins into chromatin, a highly organized and condensed structure that makes up our chromosomes. The accessibility of DNA within chromatin has implications for gene expression, so researchers have developed single-cell approaches to study chromatin accessibility at high resolution. These techniques, called single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), enable profiling of many individual cells from a single sample, but technical barriers have prevented researchers from easily combining multiple samples to speed analysis and lower costs. A research team led by Kaile Wang, Ph.D., Zhenna Xiao, Ph.D., Yun Yan and Nicholas Navin, Ph.D., developed a new single nucleus barcoding (SNuBar)-ATAC approach to easily label and combine multiple samples together for parallel sequencing. The researchers validated the approach by multiplexing 28 lung tumor samples treated with different therapy combinations as well as combining 32 different regions from a single human breast tumor. Their data suggest the approach is highly accurate, easy to use and scalable. Learn more in Molecular Cell.

Combination checkpoint blockade promotes suppressive immune microenvironment in bone metastatic prostate cancer

Prostate cancer has a “cold” immune microenvironment — with few infiltrating T cells and increased suppressive immune cells — and immune checkpoint therapies have generally provided limited benefit. Targeting the CTLA-4 immune checkpoint can increase T cells in prostate tumors, but it also leads to increases in other inhibitory checkpoints, such as PD-1/PD-L1, providing a rationale for combined checkpoint targeting. Furthermore, although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are often excluded from clinical trials. Therefore, in a Phase II pilot study led by Sumit Subudhi, M.D., Ph.D., Bilal Siddiqui, M.D., and  Padmanee Sharma, M.D., Ph.D., researchers investigated the combination of anti-CTLA-4 and anti-PD-1 therapies in 26 patients with castration-resistant prostate cancer with bone metastases. The combination therapy was safe and well tolerated, and it showed activity in a subset of patients. Studying the bone microenvironment after treatment revealed an elevation of certain inhibitory immune signals, suggesting it may be necessary to target additional pathways to overcome treatment resistance in these patients. Learn more in the Journal for ImmunoTherapy of Cancer.

ZEB1 protein speeds protein trafficking to promote motility in lung cancer cells

Epithelial-to-mesenchymal transition (EMT) is a process by which cancer cells undergo changes in gene expression to establish polarity that facilitates invasion and metastasis. This process requires fine control of many cellular processes, including protein trafficking, although details of this regulation are unclear. In a new study, a team of researchers led by Priyam Banerjee, Ph.D., Guan-Yu Xiao, Ph.D., and Jonathan Kurie, M.D., demonstrated that the EMT-activating protein ZEB1 regulates the dynamics of protein transport to create a polarity axis in lung cancer cells. Increasing ZEB1 levels accelerated endocytosis, the process by which membrane-bound proteins are internalized, and protein trafficking to lysosomes for degradation. The researchers found that ZEB1 accomplishes this by blocking microRNAs from silencing the KIF13A and AP1S2 proteins. These proteins, in turn, speed protein turnover and establish a leading edge for the cell that facilitates motility and invasiveness. Learn more in Nature Communications.

Validating immunogenic SARS-CoV-2 peptides for novel T cell therapeutic approaches

T cell responses against SARS-CoV-2 may provide durable protection against infections, and T cells targeting the virus may be useful for COVID-19 treatments. To best utilize T cells for prevention and treatment, it is critical to understand the viral targets, or peptides, that T cells recognize. To date, researchers have relied on in silico methods to predict immunogenic viral peptides, but little has been done to experimentally validate predicted targets. Researchers led by Ke Pan, Ph.D., Yulun Chiu, Ph.D., and Cassian Yee, M.D., used mass spectrometry to sequence viral peptides from the surface of infected cells and verify which could elicit T cell responses. They demonstrated that many predicted peptides are not immunogenic and should not be pursued further. The team also identified new immunogenic peptides from highly conserved viral proteins, which do not mutate frequently, offering ideal targets for therapeutic approaches. The researchers sequenced the T cell receptor (TCR) for one of these targets, allowing them to engineer the first reported TCR T cell capable of recognizing and targeting infected cells. Learn more in the Proceedings of the National Academy of Sciences.

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