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TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model
- Source :
- PLoS ONE, PLoS ONE, Vol 16, Iss 6, p e0252620 (2021)
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- Immune checkpoint inhibitors have demonstrated, over the recent years, impressive clinical response in cancer patients, but some patients do not respond at all to checkpoint blockade, exhibiting primary resistance. Primary resistance to PD-1 blockade is reported to occur under conditions of immunosuppressive tumor environment, a condition caused by myeloid derived suppressor cells (MDSCs), and by T cells exclusion, due to increased level of T regulatory cells (Tregs). Since TGF-β activates Tregs, TGF-β inhibitor may overcome primary resistance to anti-PD-1. Indeed, recent mice experiments show that combining anti-PD-1 with anti-TGF-β yields significant therapeutic improvements compared to anti-TGF-β alone. The present paper introduces two cancer-specific parameters and, correspondingly, develops a mathematical model which explains how primary resistance to PD-1 blockade occurs, in terms of the two cancer-specific parameters, and how, in combination with anti-TGF-β, anti-PD-1 provides significant benefits. The model is represented by a system of partial differential equations and the simulations are in agreement with the recent mice experiments. In some cancer patients, treatment with anti-PD-1 results in rapid progression of the disease, known as hyperprogression disease (HPD). The mathematical model can also explain how this situation arises, and it predicts that HPD may be reversed by combining anti-TGF-β to anti-PD-1. The model is used to demonstrate how the two cancer-specific parameters may serve as biomarkers in predicting the efficacy of combination therapy with PD-1 and TGF-β inhibitors.
- Subjects :
- Skin Neoplasms
Immune checkpoint inhibitors
Programmed Cell Death 1 Receptor
Cancer Treatment
Disease
CD8-Positive T-Lymphocytes
T-Lymphocytes, Regulatory
Mice
White Blood Cells
Antineoplastic Agents, Immunological
Transforming Growth Factor beta
Animal Cells
Neoplasms
Breast Tumors
Tumor Microenvironment
Medicine and Health Sciences
Medicine
Immune Checkpoint Inhibitors
Skin Tumors
Multidisciplinary
T Cells
Regulatory T cells
Oncology
Pd 1 blockade
Cellular Types
Research Article
Combination therapy
Science
Immune Cells
Immunology
Dermatology
Malignant Tumors
Gastrointestinal Tumors
Breast Cancer
Animals
Blood Cells
business.industry
Cancers and Neoplasms
Biology and Life Sciences
Cancer
Cell Biology
Models, Theoretical
medicine.disease
Blockade
Gastric Cancer
Drug Resistance, Neoplasm
Cancer research
Myeloid-derived Suppressor Cell
business
Transforming growth factor
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- PLOS ONE
- Accession number :
- edsair.doi.dedup.....f05f28dae16ca9fac937989d060c478f