Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells
| Autor: | Zhaobo Li, Kibem Kim, Ada J. Tam, Richard L. Blosser, Luis A. Diaz, Bert Vogelstein, Andrew D. Skora, Nickolas Papadopoulos, Kenneth W. Kinzler, Shibin Zhou, Liu Qiang |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Myeloid
Pyridines medicine.medical_treatment Azacitidine Programmed Cell Death 1 Receptor Epigenesis Genetic chemistry.chemical_compound Mice Cell Line Tumor medicine Animals Humans CTLA-4 Antigen Myeloid Cells Neoplasm Metastasis PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Mice Inbred BALB C Multidisciplinary biology Entinostat Antibodies Monoclonal Mammary Neoplasms Experimental Immunotherapy Biological Sciences Combined Modality Therapy Immune checkpoint Blockade Histone Deacetylase Inhibitors medicine.anatomical_structure chemistry Immunology Benzamides Cancer research biology.protein Female Antibody Colorectal Neoplasms medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 111(32) |
| ISSN: | 1091-6490 |
| Popis: | Impressive responses have been observed in patients treated with checkpoint inhibitory anti–programmed cell death-1 (PD-1) or anti–cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Here we report that treatment with both anti–PD-1 and anti–CTLA-4 antibodies was unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. Cotreatment with epigenetic-modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of the tumor-bearing mice. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K inhibitor that reduced circulating MDSCs also eradicated 4T1 tumors in 80% of the mice when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs. |
| Databáze: | OpenAIRE |
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