Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
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Authors
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
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
Document Type
Journal Article
Date
2018-04-09
Date Accepted
2018-02-15
Abstract
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.
Citation
Cancer cell, 2018, 33 (4), pp. 649 - 663.e4
Source Title
Publisher
CELL PRESS
ISSN
1535-6108
eISSN
1878-3686
Collections
Research Team
Melanoma and Kidney Cancer
Sarcoma and Melanoma Surgery
Sarcoma and Melanoma Surgery