Journal article
Anti-CTLA-4 Activates Intratumoral NK Cells and Combined with IL15/IL15Rα Complexes Enhances Tumor Control
Cancer immunology research, v 7(8), pp 1371-1380
Aug 2019
PMID: 31239316
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Antibodies targeting CTLA-4 induce durable responses in some patients with melanoma and are being tested in a variety of human cancers. However, these therapies are ineffective for a majority of patients across tumor types. Further understanding the immune alterations induced by these therapies may enable the development of novel strategies to enhance tumor control and biomarkers to identify patients most likely to respond. In several murine models, including colon26, MC38, CT26, and B16 tumors cotreated with GVAX, anti-CTLA-4 efficacy depends on interactions between the Fc region of CTLA-4 antibodies and Fc receptors (FcR). Anti-CTLA-4 binding to FcRs has been linked to depletion of intratumoral T regulatory cells (Treg). In agreement with previous studies, we found that Tregs infiltrating CT26, B16-F1, and autochthonous
melanoma tumors had higher expression of surface CTLA-4 (sCTLA-4) than other T-cell subsets, and anti-CTLA-4 treatment led to FcR-dependent depletion of Tregs infiltrating CT26 tumors. This Treg depletion coincided with activation and degranulation of intratumoral natural killer cells. Similarly, in non-small cell lung cancer (NSCLC) and melanoma patient-derived tumor tissue, Tregs had higher sCTLA-4 expression than other intratumoral T-cell subsets, and Tregs infiltrating NSCLC expressed more sCTLA-4 than circulating Tregs. Patients with cutaneous melanoma who benefited from ipilimumab, a mAb targeting CTLA-4, had higher intratumoral CD56 expression, compared with patients who received little to no benefit from this therapy. Furthermore, using the murine CT26 model we found that combination therapy with anti-CTLA-4 plus IL15/IL15Rα complexes enhanced tumor control compared with either monotherapy.
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Details
- Title
- Anti-CTLA-4 Activates Intratumoral NK Cells and Combined with IL15/IL15Rα Complexes Enhances Tumor Control
- Creators
- Emilio Sanseviero - The Wistar InstituteErin M O'Brien - Immunology, Microenvironment and Metastasis Program, Wistar Cancer Center, The Wistar Institute, Philadelphia, PennsylvaniaJenna R Karras - The Wistar InstituteTamer B Shabaneh - Dartmouth CollegeBulent Arman Aksoy - Medical University of South CarolinaWei Xu - University of PennsylvaniaCathy Zheng - University of PennsylvaniaXiangfan Yin - The Wistar InstituteXiaowei Xu - University of PennsylvaniaGiorgos C Karakousis - University of PennsylvaniaRavi K Amaravadi - University of PennsylvaniaBrian Nam - Christiana Care Health SystemMary Jo Turk - Dartmouth CollegeJeff Hammerbacher - Medical University of South CarolinaMark P Rubinstein - Medical University of South CarolinaLynn M Schuchter - University of PennsylvaniaTara C Mitchell - University of PennsylvaniaQin Liu - The Wistar InstituteErica L Stone - Immunology, Microenvironment and Metastasis Program, Wistar Cancer Center, The Wistar Institute, Philadelphia, Pennsylvania. estone@gigagen.com
- Publication Details
- Cancer immunology research, v 7(8), pp 1371-1380
- Publisher
- American Association for Cancer Research (AACR)
- Grant note
- R01 CA225028 / NCI NIH HHS R21 CA209375 / NCI NIH HHS R01 CA205965 / NCI NIH HHS P30 CA010815 / NCI NIH HHS P50 CA174523 / NCI NIH HHS K01 DK095008 / NIDDK NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000478015500014
- Scopus ID
- 2-s2.0-85070561383
- Other Identifier
- 991019167568504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology
- Oncology