Zeb1 Induces Immune Checkpoints to Form an Immunosuppressive Envelope Around Invading Cancer Cells

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 May 22

PMID 34020945

Citations 37

Authors

Yan Guo

Xiaoqin Lu

Yao Chen

Beatriz Rendon

Robert A Mitchell

Miriam Cuatrecasas

Marlies Cortes

Antonio Postigo

Yongqing Liu

Douglas C Dean

Affiliations

Soon will be listed here.

Abstract

The PDL1-PD1 immune checkpoint inhibits T cell activation, and its blockade is effective in a subset of patients. Studies are investigating how checkpoints are hijacked by cancer cells and why most patients remain resistant to immunotherapy. Epithelial mesenchymal transition (EMT), which drives tumor cell invasion via the Zeb1 transcription factor, is linked to immunotherapy resistance. In addition, M2-polarized tumor-associated macrophages (TAMs), which inhibit T cell migration and activation, may also cause immunotherapy resistance. How EMT in invading cancer cells is linked to therapy resistance and events driving TAM M2 polarization are therefore important questions. We show that Zeb1 links these two resistance pathways because it is required for PDL1 expression on invading lung cancer cells, and it also induces CD47 on these invading cells, which drives M2 polarization of adjacent TAMs. Resulting reprogramming of the microenvironment around invading cells shields them from the hostile inflammatory environment surrounding tumors.

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