Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells

Xiangnan Guan, Ruozhen Hu, Yoonha Choi, Shyam Srivats, Barzin Y. Nabet, John Silva, Lisa McGinnis, Robert Hendricks, Katherine Nutsch, Karl L. Banta, Ellen Duong, Alexis Dunkle, Patrick S. Chang, Chia-Jung Han, Stephanie Mittman, Nandini Molden, Pallavi Daggumati, Wendy Connolly, Melissa Johnson, Delvys Rodriguez Abreu, Byoung Chul Cho, Antoine Italiano, Ignacio Gil-Bazo, Enriqueta Felip, Ira Mellman, Sanjeev Mariathasan, David S. Shames, Raymond Meng, Eugene Y. Chiang, Robert J. Johnston () and Namrata S. Patil ()
Additional contact information
Xiangnan Guan: Genentech Inc.
Ruozhen Hu: Genentech Inc.
Yoonha Choi: Genentech Inc.
Shyam Srivats: Genentech Inc.
Barzin Y. Nabet: Genentech Inc.
John Silva: Genentech Inc.
Lisa McGinnis: Genentech Inc.
Robert Hendricks: Genentech Inc.
Katherine Nutsch: Genentech Inc.
Karl L. Banta: Genentech Inc.
Ellen Duong: Genentech Inc.
Alexis Dunkle: Genentech Inc.
Patrick S. Chang: Genentech Inc.
Chia-Jung Han: Genentech Inc.
Stephanie Mittman: Genentech Inc.
Nandini Molden: Genentech Inc.
Pallavi Daggumati: Genentech Inc.
Wendy Connolly: Genentech Inc.
Melissa Johnson: Sarah Cannon Research Institute/Tennessee Oncology, PLLC
Delvys Rodriguez Abreu: Hospital Universitario Insular de Gran Canaria
Byoung Chul Cho: Yonsei University College of Medicine
Antoine Italiano: Institut Bergonie CLCC Bordeaux
Ignacio Gil-Bazo: CIMA Universidad de Navarra Pamplona
Enriqueta Felip: Vall d’Hebron Institute of Oncology (VHIO)
Ira Mellman: Genentech Inc.
Sanjeev Mariathasan: Genentech Inc.
David S. Shames: Genentech Inc.
Raymond Meng: Genentech Inc.
Eugene Y. Chiang: Genentech Inc.
Robert J. Johnston: Genentech Inc.
Namrata S. Patil: Genentech Inc.

Nature, 2024, vol. 627, issue 8004, 646-655

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07121-9

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