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Effective Anti-tumor Response by TIGIT Blockade Associated With FcγR Engagement and Myeloid Cell Activation
- Source :
- Frontiers in Immunology, Vol 11 (2020), Frontiers in Immunology
- Publication Year :
- 2020
- Publisher :
- Frontiers Media S.A., 2020.
-
Abstract
- The molecule "T cell immunoreceptor with immunoglobulin and ITIM domain," or TIGIT, has recently received much attention as a promising target in the treatment of various malignancies. In spite of the quick progression of anti-TIGIT antibodies into clinical testing both as monotherapy and in combination with programmed cell death-1 (PD-1)-directed immune checkpoint blockade, the molecular mechanism behind the observed therapeutic benefits remains poorly understood. Here we demonstrate, using mouse tumor models, that TIGIT blocking antibodies with functional Fc binding potential induce effective anti-tumor response. Our observations reveal that the anti-TIGIT therapeutic effect is not achieved by depletion of intratumoral regulatory T cells (Treg) or any cell population expressing TIGIT, but instead is mediated by possible "reverse activating signals" through FcγRs on myeloid cells, inducing expression of various mediators such as cytokines and chemokines. Furthermore, we discovered an induction of a robust and persistent granzyme B and perforin response, distinct from a predominantly interferon-γ (IFN-γ)-driven anti-PD-1 blockade. Our observations, for the first time, provide the basis for a mechanistic hypothesis involving the requirement of a functional Fc domain of anti-TIGIT monoclonal antibodies, of which various isotypes are currently under intense clinical investigation.
- Subjects :
- 0301 basic medicine
Programmed Cell Death 1 Receptor
combination cancer immunotherapy
Granzymes
Antineoplastic Agents, Immunological
0302 clinical medicine
FcγR
Tumor Microenvironment
Immunology and Allergy
Receptors, Immunologic
Immune Checkpoint Inhibitors
Original Research
Mice, Knockout
Mice, Inbred BALB C
education.field_of_study
Antibodies, Monoclonal
Tumor Burden
medicine.anatomical_structure
myeloid cells
Colonic Neoplasms
Female
costimulatory molecules
Antibody
Signal Transduction
Pore Forming Cytotoxic Proteins
lcsh:Immunologic diseases. Allergy
medicine.drug_class
TIGIT
T cell
Immunology
Population
Biology
Monoclonal antibody
03 medical and health sciences
Cell Line, Tumor
medicine
Animals
education
Receptors, IgG
Correction
immune checkpoint blockade
Immune checkpoint
Blockade
Mice, Inbred C57BL
Granzyme B
030104 developmental biology
Cancer research
biology.protein
lcsh:RC581-607
030215 immunology
Subjects
Details
- Language :
- English
- ISSN :
- 16643224
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Frontiers in Immunology
- Accession number :
- edsair.doi.dedup.....d1d8bcb57f3ccabc04caba515eab3fa9