DNASE1L3 enhances antitumor immunity and suppresses tumor progression in colon cancer.

JCI insight 2023 Sep 08

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DNASE1L3, an enzyme highly expressed in DCs, is functionally important for regulating autoimmune responses to self-DNA and chromatin. Deficiency of DNASE1L3 leads to development of autoimmune diseases in both humans and mice. However, despite the well-established causal relationship between DNASE1L3 and immunity, little is known about the involvement of DNASE1L3 in regulation of antitumor immunity, the foundation of modern antitumor immunotherapy. In this study, we identify DNASE1L3 as a potentially new regulator of antitumor immunity and a tumor suppressor in colon cancer. In humans, DNASE1L3 is downregulated in tumor-infiltrating DCs, and this downregulation is associated with poor patient prog nosis and reduced tumor immune cell infiltration in many cancer types. In mice, Dnase1l3 deficiency in the tumor microenvironment enhances tumor formation and growth in several colon cancer models. Notably, the increased tumor formation and growth in Dnase1l3-deficient mice are associated with impaired antitumor immunity, as evidenced by a substantial reduction of cytotoxic T cells and a unique subset of DCs. Consistently, Dnase1l3-deficient DCs directly modulate cytotoxic T cells in vitro. To our knowledge, our study unveils a previously unknown link between DNASE1L3 and antitumor immunity and further suggests that restoration of DNASE1L3 activity may represent a potential therapeutic approach for anticancer therapy.

Citation

Wenling Li, Hideki Nakano, Wei Fan, Yuanyuan Li, Payel Sil, Keiko Nakano, Fei Zhao, Peer W Karmaus, Sara A Grimm, Min Shi, Xin Xu, Ryushin Mizuta, Daisuke Kitamura, Yisong Wan, Michael B Fessler, Donald N Cook, Igor Shats, Xiaoling Li, Leping Li. DNASE1L3 enhances antitumor immunity and suppresses tumor progression in colon cancer. JCI insight. 2023 Sep 08;8(17)