Pannexin1 channel-dependent secretome from apoptotic tumor cells shapes immune-escape microenvironment

Apoptotic cell death is a critical step in organism development and tissue homeostasis. Apoptotic cells affect immune cell activities in normal tissues. It is not clear whether similar cell death machinery causes tumor environments to evade anti-tumor immune responses. Here, using a mouse transplant model, we found a large number of tumor cells undergoing intrinsic apoptosis in tumors derived from the 4T1 breast cancer cell line, where neutrophils significantly accumulated. Interestingly, these apoptotic 4T1 tumor cells directly induced neutrophil extracellular traps (NETs) in a pannexin 1 (Panx1) channeldependent manner, and knockdown of Panx1 in 4T1 cells led to a reduction in tumor size. Spermidine released through Panx1 from apoptotic 4T1 cells induced NETs in bone marrow-derived neutrophils in vitro. In addition, inhibition of spermidine synthesis suppressed tumor growth in the mouse transplant model. Collectively, our data suggested a new immune-escape mechanism for tumors by Panx1mediated secretome from intrinsic apoptotic cells, which may provide a new therapeutic target for cancer.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

This study identified a new immune-escape mechanism for tumors involving the secretion of Panx1-dependent extracellular traps by apoptotic tumor cells. Inhibition of this mechanism may offer a new therapeutic target for cancer treatment.