Nature, volume 627, issue 8004, pages 646-655
Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells
Xiangnan Guan
1
,
Ruozhen Hu
1
,
Yoonha Choi
1
,
Shyam Srivats
1
,
Barzin Y Nabet
1
,
John Silva
1
,
Lisa Mcginnis
1
,
Robert Hendricks
1
,
Katherine Nutsch
1
,
Karl L Banta
1
,
Ellen Duong
1
,
Alexis Dunkle
1
,
Patrick Chang
1
,
Chia-Jung Han
1
,
Stephanie Mittman
1
,
Nandini Molden
1
,
Pallavi Daggumati
1
,
Wendy Connolly
1
,
Delvys Rodriguez-Abreu
3
,
Byoung Jun Cho
4
,
Antoine Italiano
5, 6
,
Ignacio Gil-Bazo
7
,
Enriqueta Felip
8
,
I. S. Mellman
1
,
Sanjeev MARIATHASAN
1
,
David S. Shames
1
,
Raymond Meng
1
,
Eugene Y. Chiang
1
,
Robert J. Johnston
1
,
Namrata Patil
1
1
Genentech Inc., South San Francisco, USA
|
2
Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, USA
|
3
Hospital Universitario Insular De Gran Canaria, Las Palmas, Spain
|
5
Institut Bergonie CLCC Bordeaux, Bordeaux, France
|
8
Vall D’Hebron Institute of Oncology (VHIO), Barcelona, Spain
|
Publication type: Journal Article
Publication date: 2024-02-28
Journal:
Nature
scimago Q1
wos Q1
SJR: 18.509
CiteScore: 90.0
Impact factor: 50.5
ISSN: 00280836, 14764687
Multidisciplinary
Abstract
Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone1. However, there remains little consensus on the mechanism(s) of response with this combination2. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8+ T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development. A high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients with non-small cell lung cancer treated with atezolizumab plus tiragolumab, but not with atezolizumab alone.
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