Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
View/ Open
Date
2018-04-09Author
Arce Vargas, F
Furness, AJS
Litchfield, K
Joshi, K
Rosenthal, R
Ghorani, E
Solomon, I
Lesko, MH
Ruef, N
Roddie, C
Henry, JY
Spain, L
Ben Aissa, A
Georgiou, A
Wong, YNS
Smith, M
Strauss, D
Hayes, A
Nicol, D
O'Brien, T
Mårtensson, L
Ljungars, A
Teige, I
Frendéus, B
TRACERx Melanoma,
TRACERx Renal,
TRACERx Lung consortia,
Pule, M
Marafioti, T
Gore, M
Larkin, J
Turajlic, S
Swanton, C
Peggs, KS
Quezada, SA
Type
Journal Article
Metadata
Show full item recordAbstract
With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.
Collections
Subject
TRACERx Melanoma
TRACERx Renal
TRACERx Lung consortia
Cell Line, Tumor
Animals
Humans
Mice
Melanoma
Receptors, IgG
Antibodies, Monoclonal
Treatment Outcome
Xenograft Model Antitumor Assays
Polymorphism, Single Nucleotide
Female
T-Lymphocytes, Regulatory
CTLA-4 Antigen
Antibodies, Monoclonal, Humanized
Antineoplastic Agents, Immunological
Ipilimumab
Research team
Melanoma and Kidney Cancer
Sarcoma and Melanoma Surgery
Language
eng
Date accepted
2018-02-15
License start date
2018-04
Citation
Cancer cell, 2018, 33 (4), pp. 649 - 663.e4
Publisher
CELL PRESS
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
Related items
Showing items related by title, author, creator and subject.
-
Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.
Arce Vargas, F; Furness, AJS; Solomon, I; Joshi, K; Mekkaoui, L; et al. (CELL PRESS, 2017-04-18)CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We ... -
RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma.
East, P; Kelly, GP; Biswas, D; Marani, M; Hancock, DC; et al. (NATURE PORTFOLIO, 2022-09-26)Activating mutations in KRAS occur in 32% of lung adenocarcinomas (LUAD). Despite leading to aggressive disease and resistance to therapy in preclinical studies, the KRAS mutation does not predict patient outcome or response ... -
Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.
Mitchell, TJ; Turajlic, S; Rowan, A; Nicol, D; Farmery, JHR; et al. (CELL PRESS, 2018-04-19)Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with ...