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조회379

최윤하Yoonha Choi

Genentech Inc.

Nature, Feb 28 2024, | https://doi.org/10.1038/s41586-024-07121-9 Anti-TIGIT antibody improves PD-L1 blockade through myeloid and Treg cells

Xiangnan Guan^1,9, Ruozhen Hu^1,9, Yoonha Choi^1,9, Shyam Srivats^1,9, Barzin Y. Nabet¹, John Silva¹, Lisa McGinnis¹, Robert Hendricks¹, Katherine Nutsch¹, Karl L. Banta¹, Ellen Duong¹, Alexis Dunkle¹, Patrick S. Chang¹, Chia-Jung Han¹, Stephanie Mittman¹, Nandini Molden¹, Pallavi Daggumati¹, Wendy Connolly¹, Melissa Johnson², Delvys Rodriguez Abreu³, Byoung Chul Cho⁴, Antoine Italiano^5,6, Ignacio Gil-Bazo⁷, Enriqueta Felip⁸, Ira Mellman¹, Sanjeev Mariathasan¹, David S. Shames¹, Raymond Meng¹, Eugene Y. Chiang¹, Robert J. Johnston^1,9,10 & Namrata S. Patil^1,9,10

¹Genentech Inc., South San Francisco, CA, USA.

²Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA.

³Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain.

⁴Yonsei Cancer Centre, Yonsei University College of Medicine, Seoul, South Korea.

⁵Institut Bergonie CLCC Bordeaux, Bordeaux, France.

⁶Faculty of Medicine, University of Bordeaux, Bordeaux, France.

⁷Clínica Universidad de Navarra, CIMA Universidad de Navarra Pamplona, Pamplona, Spain.

⁸Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain.

⁹These authors contributed equally: Xiangnan Guan, Ruozhen Hu, Yoonha Choi, Shyam Srivats, Robert J. Johnston, Namrata S. Patil.

¹⁰These authors jointly supervised this work: Robert J. Johnston, Namrata S. Patil.

Corresponding authors : Correspondence to Robert J. Johnston or Namrata S. Patil.

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 alone ¹. However, there remains little consensus on the mechanism(s) of response with this combination ². 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.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-03-06)
연구진국외 연구진
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