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
Show full list: 31 authors
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 typeJournal Article
Publication date2024-02-28
Journal: Nature
scimago Q1
wos Q1
SJR18.509
CiteScore90.0
Impact factor50.5
ISSN00280836, 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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