UCSD - University of California - San Diego
09/04/2025 | Press release | Distributed by Public on 09/04/2025 12:44
Cancer Breakthrough Sparks New Vaccine
Story by:
- Miles Martin- [email protected]
Published Date
September 04, 2025Article Content
Immune-checkpoint therapy (ICT), which attempts to harness a patient's own immune system to fight cancer, has revolutionized cancer care over the past two decades. However, many patients do not respond to this therapy, and drug resistance due to immune-evasive (or 'cold') tumors remains poorly understood.
"Identifying likely non-responders and mechanisms behind this resistance is crucial to guiding precision ICT, developing more effective personalized treatments, and avoiding severe costs of ineffective therapy," said Scott Lippman M.D. Distinguished Professor of Medicine and academic director of the M.S. program in Precision Medicine at University of California San Diego School of Medicine. Now, Lippman, who is also a member of UC San Diego's Center for Engineering and Cancer and Moores Cancer Center, has spearheaded a new study, published this week as a Special Article and also featured as the cover story for the September issue of the Journal of Thoracic Oncology, that offers new insight into this fundamental challenge in oncology. The research has also sparked the development of a new cancer vaccine that could make ICT more effective.
Dendritic Cell (DC) Vaccine Override. Diagram shows exogenous CXCL9/10 DC vaccine override of 9p-loss chemokine depletion; it promotes a CXCR3+ T-cell cascade, releases IFN-γ, and triggers endogenous CXCL9/10 signals to fight cancer. Credit: S. Lippman, C. Eng.
Genetic Foundations
A previous study of ICT resistance from Lippman's lab provided the foundation for the new report. In 2021, his group first reported that in certain head and neck cancers, specific genetic changes on the short, so-called 'p', arm of chromosome 9 is the biggest driver of ICT nonresponse. Specifically, they focused on the human papillomavirus (HPV)- subtype of head and neck squamous cancer, which is the most common and lethal form of the disease.
In this type of cancer, the researchers found that loss of one or both copies of 9p, or parts thereof, was the singular, most profound driver of immune-evasion and ICT resistance across every possible chromosomal loss or gain. This discovery sparked a wave of new research documenting 15-20% 9p chromosomal copy-number loss and ICT resistance, with more than 10 groups across the country confirming the head and neck findings and extending them to subsets of lung, mesothelioma, melanoma and bladder cancer.
"Our results were utilized by the nation's largest clinical laboratories to support the Clinical Laboratory Improvement Amendments (CLIA) accuracy requirement in developing Medicare-covered 9p ICT-predictive tests, and is progressively defining the genomic basis of responsiveness to the most employed forms of oncologic therapeutics," said Lippman, referring to standard clinical biomarker tests that can be used to help predict whether ICT will be effective. Today, these tests apply to certain other cancers in which loss-of-9p, immune-evasion exists, notably non-squamous non-small cell lung cancer.
The 2021 article also found that while 9p harbors many immune-regulatory genes, the consequence of 9p loss is indirect, causing a sharp reduction in important signaling molecules called cytokines -particularly CXCL9 and CXCL10. These molecules are actually encoded in an entirely different part of the genome, far away from 9p. In an exploratory analysis of bulk RNA sequencing (RNA-seq) dataset covering 17,187 human genes, 9p loss was linked to an extreme scarcity of the CXCR3 chemokine family, which includes CXCL9, CXCL10, and CXCL11. In fact, CXCL10 and CXCL11 were, remarkably, the two most suppressed genes in the entire dataset.
"These data told us we were onto something important," he noted. "The pivotal role of CXCL9/10 in tumor microenvironment (TME) programming and these initial 9p RNA-seq findings generated intense interest in the cellular sources and regulation of these chemokines."
For the new study, Lippman brought together four research groups from across the country to undertake a tour-de-force investigation focused on how specific genomic changes influence and interact with CXCL9/10 chemokines. Encompassing 3 publicly-available large-scale genomic datasets, 76 cell lines, 38 tumor types, and 2 genetically-engineered mouse models, this work has led to the development of a new immune-cell vaccine that could re-program the TME in 9p-loss tumors.
The Molecular Culprit
While the initial study helped scientists understand what happens in tumors without 9p, what it didn't explain was which genes led to this effect, which is essential to figuring out how to reverse it. Perhaps the most stunning results from this new work involve type-I interferon-I (IFN-I) genes, which have been historically underappreciated in cancer immunology research, in contrast to their type-II counterpart, IFNG, which has been more thoroughly studied by cancer researchers. All the genes that encode human type-I interferons-17 genes in total- are found on chromosome 9p on two neighboring loci (sections) 9p21.3 and 9p21.2. The new results nominate IFN-I gene losses at 9p21 as a pervasive mechanism of immune evasion, rivaling previously-known mechanisms related to HLA-cluster losses at 6p21.
"We found that IFN-I deficiency contributes to an immune-deserted state making it harder for immune cells to infiltrate tumors and produce certain chemokines, primarily CXCL9/10, which are IFN-γ inducible essential for attracting activated T-cells to the tumor site," said Teresa Davoli, Ph.D., co-senior author and associate professor at New York University's Grossman School of Medicine.
To probe the mechanistic link between 9p loss, IFN-I, and CXCL9/10, the researchers analyzed RNA-sequencing data from mouse pancreatic tumors that had been engineered to be missing parts of 9p21.3.
"We quantified immune-cell types, subtypes, and subclusters expressing CXCL9/10, measuring their numbers, fractions, per-cell expression, and spatial distribution," said study coauthor Kaloyan Tsanov, Ph.D., formerly of Memorial Sloan Kettering Cancer Center and now assistant professor at the University of Chicago. The researchers found a direct correlation between tumor IFN-I status and both the abundance and expression of CXCL9/10+ immune cells: The genetic loss of interferons in tumor cells reduced CXCL9/10 levels, the number of CXCL9/10+ immune cells, and subcluster heterogeneity. The researchers were also able to pinpoint a specific subtype of IFN-I, called IFNε, as the predominant cell-intrinsic type-I IFN operative in, and the direct link between, 9p-loss profound tissue-specific effector T-cell loss, and suppression of cytokine (e.g., IFN-γ), including CXCL9/10, pathways.
"Thus, interferon genes-notably including the poorly studied IFNE-provide a potent tumor-derived signal to a major source of CXCL9/10," Tsanov added.
Not By Chance
Diagram compares 3 tumor microenvironments:active immune defense, immune suppression from 9p chromosome loss, and restored immunity in 9p loss tumors with CXCL mechanism through engineered vaccine response. Credit: S. Lippman, C. Eng.
In addition to identifying the molecular source of ICT resistance, another question researchers were able to address is why ICT resistance is relatively common to begin with. Typically, cells have two copies of each chromosome, and losing both copies (homozygous deletion) is rare, but the researchers found that compared to all other human chromosome arms, tumors missing 9p more often lose both copies. Data from the Pan-Cancer Analysis of Whole-Genomes project confirmed the importance of 9p loss in cancer, where it was discovered that 9p was the most frequent homozygously-deleted arm.
"Remarkably, 9p was one of only two arms, the other being 12q, where median homozygous deletion length actually exceeded heterozygous lengths," said coauthor Azhar Khandekar, a joint graduate student at UC San Diego and the National Cancer Institute. Notably, these two arms with comparatively more homozygous deletions also happen to be where interferon genes are located: 9p for IFN-I and 12q for IFN-II.
"These findings suggest that there is strong selective pressure for deep deletions of interferon genes, likely to drive tumor immune-evasion," says Khandekar. In other words, these genomic alterations aren't chance occurrences, but instead evolutionary adaptations allowing cancer cells to evade the immune system, rendering ICT ineffective.
A New Vaccine
Together, these findings could have substantial implications for personalizing cancer treatment, particularly with cancer vaccines, which are somewhat similar to ICT insofar as they both target the immune system. However, cancer vaccines are more specific in their approach, often targeting specific tumor antigens or pathways, whereas ICT treatments have a more general mechanism of action, releasing the brakes on the immune system to attack cancer cells.
"This report provides important new insights into the regulation of CXCL9/10, offering a level of granularity not previously described in the literature," said study coauthor Steve Dubinett, M.D., dean of the David Geffen School of Medicine at UC Los Angeles. "By characterizing CXCL9+ and CXCL10+ immune-cell subcluster numbers and expression at single-cell resolution, the study reveals that tumor-intrinsic type-I interferon signaling may drive differential host antitumor immune activation through downstream CXCL9 and/or CXCL10 pathways, providing strong rationale for the use of these chemokines therapeutically for patients whose tumors evidence 9p-loss immune-evasive tumors."
To leverage this tumor immunology in the clinic, Dubinett's team created a vaccine, using engineered immune cells called dendritic cells (DC), to bypass CXCL9/10 depletion and trigger an anti-tumor immune response in 9p-loss tumors. Tested successfully in mice, this approach was reported several months ago. However, as Dubinett notes, "further research is needed to reveal the clinical potential of this DC vaccine in 9p-loss tumors."
MACHETE-engineered deletions of type-I interferon genes. Highlights synteny (homology) at human 9p21.3/mouse 4C4 locus. MACHETE also can dissect other key human 9p genes, such as IFNγ-pathway gene JAK2 at 9p24.1 (mouse 19C1) and beyond. Credit: S. Lippman, C. Eng.
While it will take more work to see this approach leveraged in the clinic, the researchers are excited about the possibilities this breakthrough represents.
"This is a huge step forward for personalized immune cancer therapy," added Lippman.
Additional coauthors of the study include: Xin Zhao, and Maria Trifas, from New York University Langone Health; William N. William from UC San Diego and Oncoclínicas São Paulo; Bin Liu, PhD, Raymond J. Lim, and Yushen Du from UCLA Jonsson Comprehensive Cancer Center and Yu-Jui Ho, Francisco M. Barriga, and Scott W. Lowe from Memorial Sloan Kettering Cancer Center.
This study was funded, in part, by the National Institutes of Health (grants K99 CA266939, R01DE026644, U01CA0290479, P01 CA106451, P50 CA097007, P30 CA023100, R37CA248631, and R01HG012590), the Jane Coffin Childs Memorial Fund for Medical Research, Memorial Sloan Kettering Cancer Center (grants 5T32CA160001 and David Rubenstein Center for Pancreatic Research Pilot Project), the Gerry Metastasis and Tumor Ecosystems Center (GMTEC) (Postdoctoral Fellowship and Classic Individual Funding), the Edward P. Evans Foundation (Young Investigator Award), the Tobacco Related Disease Research Program (grant T30DT0963), the Howard Hughes Medical Institute, the Geoffrey Beene Chair for Cancer Biology, the Agilent Thought Leader Program, the UCLA Technology Development Group Innovation Fund, the NCI Early Detection Research Network (grant 1U2CCA271898), the Department of Veterans Affairs (grants 1I50CU000157), Cancer Research UK (grant C67321/ A29060), and Stand up to Cancer.
Disclosures: Scott Lowe receives consultant fees and holding equity in Blueprint Medicines, ORIC Pharmaceuticals, Mirimus, PMV Pharmaceuticals, Faeth Therapeutics, Senescea Therapeutics and Constellation Pharmaceuticials. Steven Dubinett receives research funds from Janssen and Novartis, stock options and is on the advisory board of Lung Life AI, Inc. and Early Diagnostics, Inc. Teresa Davoli is a member of the SAB of io9 (now Acurion) and KaryoVerse therapeutics. Scott Lippman has served in an advisory capacity for, and received stock options from Sympto Health, Biological Dynamics; he is a cofounder of io9 LLC (now Acurion, Inc.); and is a co-inventor of IP related to genomic (9p) predictive biomarkers and precision immunotherapy: Title: Methods and Biomarkers in Cancer (inst) to Davoli and Lippman, PCT/U.S. Provisional Application Serial No. 63/483,237; and Title: Artificial Intelligence Architecture for Predicting Cancer Biomarkers (inst) to Lippman and Alexandrov, U.S. Provisional Application Serial No. 63/412,835, U.S. Provisional Application Serial No. 63/412,835 Title: Genetically-Defined Immune-Checkpoint Inhibitor Resistance in Aggressive Precursors of HPV- Head and Neck Squamous Cancer. All other authors report no disclosures.
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