Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer

Lucia Taraborrelli, Yasin Şenbabaoğlu, Lifen Wang, Junghyun Lim, Kerrigan Blake, Noelyn Kljavin, Sarah Gierke, Alexis Scherl, James Ziai, Erin McNamara, Mark Owyong, Shilpa Rao, Aslihan Karabacak Calviello, Daniel Oreper, Suchit Jhunjhunwala, Guillem Argiles, Johanna Bendell, Tae Won Kim, Fortunato Ciardiello, Matthew J. Wongchenko, Frederic J. Sauvage, Felipe Sousa e Melo, Yibing Yan, Nathaniel R. West () and Aditya Murthy ()
Additional contact information
Lucia Taraborrelli: Genentech Inc.
Yasin Şenbabaoğlu: Genentech Inc.
Lifen Wang: Genentech Inc.
Junghyun Lim: Genentech Inc.
Kerrigan Blake: Genentech Inc.
Noelyn Kljavin: Genentech Inc.
Sarah Gierke: Genentech Inc.
Alexis Scherl: Genentech Inc.
James Ziai: Genentech Inc.
Erin McNamara: Genentech Inc.
Mark Owyong: Genentech Inc.
Shilpa Rao: Genentech Inc.
Aslihan Karabacak Calviello: Genentech Inc.
Daniel Oreper: Genentech Inc.
Suchit Jhunjhunwala: Genentech Inc.
Guillem Argiles: Vall d’Hebrón University Hospital, Universitat Autònoma de Barcelona
Johanna Bendell: Sarah Cannon Research Institute/Tennessee Oncology
Tae Won Kim: University of Ulsan
Fortunato Ciardiello: Università degli Studi della Campania Luigi Vanvitelli
Matthew J. Wongchenko: Genentech, Inc.
Frederic J. Sauvage: Genentech Inc.
Felipe Sousa e Melo: Genentech Inc.
Yibing Yan: Genentech, Inc.
Nathaniel R. West: Genentech Inc.
Aditya Murthy: Genentech Inc.

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Microsatellite-stable colorectal cancer (MSS-CRC) is highly refractory to immunotherapy. Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve MSS-CRC patient outcomes. Here, we demonstrate that high tumor expression of the core autophagy gene ATG16L1 is associated with poor clinical response to anti-PD-L1 therapy in KRAS-mutant tumors from IMblaze370 (NCT02788279), a large phase III clinical trial of atezolizumab (anti-PD-L1) in advanced metastatic MSS-CRC. Deletion of Atg16l1 in engineered murine colon cancer organoids inhibits tumor growth in primary (colon) and metastatic (liver and lung) niches in syngeneic female hosts, primarily due to increased sensitivity to IFN-γ-mediated immune pressure. ATG16L1 deficiency enhances programmed cell death of colon cancer organoids induced by IFN-γ and TNF, thus increasing their sensitivity to host immunity. In parallel, ATG16L1 deficiency reduces tumor stem-like populations in vivo independently of adaptive immune pressure. This work reveals autophagy as a clinically relevant mechanism of immune evasion and tumor fitness in MSS-CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.

Date: 2023
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DOI: 10.1038/s41467-023-41618-7

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