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

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. © 2023. Springer Nature Limited.

Citation

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 de Sauvage, Felipe de Sousa E Melo, Yibing Yan, Nathaniel R West, Aditya Murthy. Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer. Nature communications. 2023 Sep 23;14(1):5945

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PMID: 37741832

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