Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte activation gene-3 (LAG3) signaling is regulated by a disintegrin and metalloprotease domain-containing protein-10 (ADAM10)- and ADAM17-mediated cell surface shedding. Here, we show that mice expressing a metalloprotease-resistant, noncleavable LAG3 mutant (LAG3) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3 intrinsically perturbs CD4 T conventional cells (T), limiting their capacity to provide CD8 T cell help. Furthermore, the translational relevance for these observations is highlighted with an inverse correlation between high LAG3 and low ADAM10 expression on CD4 T in the peripheral blood of patients with head and neck squamous cell carcinoma, which corresponded with poor prognosis. This correlation was also observed in a cohort of patients with skin cancers and was associated with increased disease progression after standard-of-care immunotherapy. These data suggest that subtle changes in LAG3 inhibitory receptor signaling can act as a resistance mechanism with a substantive effect on patient responsiveness to immunotherapy.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901539 | PMC |
| http://dx.doi.org/10.1126/sciimmunol.abc2728 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
SMAC-armed oncolytic virotherapy enhances the anticancer activity of PD1 blockade by modulating PANoptosis.
Biomark Res
January 2025
Department of Hematology and Medical Oncology, Emory University, 201 Dowman Dr, Atlanta, GA, 30322, USA.
Background: Oncolytic viruses (OVs) are increasingly recognized as promising tools for cancer therapy, as they selectively infect and destroy tumor cells while leaving healthy cells unharmed. Despite considerable progress, the limited therapeutic efficacy of OV-based virotherapy continues to be a significant challenge in cancer treatment.
Methods: The SMAC/DIABLO gene was inserted into the genome of vesicular stomatitis virus (VSV) to generate VSV-S.
TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids.
Cancer Immunol Res
January 2025
Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR) T cells as a treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to resistance to CAR T-cell therapy in solid tumors, and appropriate model systems to identify and examine these factors using clinically relevant biospecimens are limited. In this study, we examined the activity of B7-H3-directed CAR T cells (B7-H3.
View Article and Find Full Text PDFPrognostic Features and Potential for Immune Therapy in Metastatic Mismatch Repair-Deficient Colorectal Cancer: A Retrospective Analysis of a Large Consecutive Population-Based Patient Series.
Cancer Med
January 2025
Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland.
Background: Immune checkpoint inhibition therapies have provided remarkable results in numerous metastatic cancers, including mismatch repair-deficient (dMMR) colorectal cancer (CRC). To evaluate the potential for PD-1 blockade therapy in a large population-based cohort, we analyzed the tumor microenvironment and reviewed the clinical data and actualized treatment of all dMMR CRCs in Central Finland province between 2000 and 2015.
Material And Methods: Of 1343 CRC patients, 171 dMMR tumors were identified through immunohistochemical screening.
Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment.
J Immunother Cancer
January 2025
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA
Background: Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios.
Methods: Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models respond and pancreatic ductal adenocarcinoma (PDAC) progresses.
Circulating microRNAs as a Prognostic Tool to Determine Treatment Efficacy in Lung Cancer Patients Undergoing Pembrolizumab PD-1 Blockade Immunotherapy.
Cancers (Basel)
December 2024
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA.
Pembrolizumab has recently emerged as a PD-1 blockade immunotherapy treatment for lung cancer. It is critical that such treatment strategies for lung cancer should be chosen not only on the basis of histopathological features and the expression of targetable cell surface proteins (such as PD-1), but should rather be selected based on other determinants of treatment success or risk factors for poor prognosis. One method to forecast cancer trajectory is the identification of biomolecular signatures such as microRNAs (miRNAs), non-protein-coding RNA molecules that play a regulatory role in gene expression by modulating the translation or stability of messenger RNA.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!