Crk adaptor protein promotes PD-L1 expression, EMT and immune evasion in a murine model of triple-negative breast cancer

Oncoimmunology
Sushil KumarRaymond B Birge

Abstract

The tumor infiltration of immune cells in solid cancers can profoundly influence host antitumor responses. In recent years, immunotherapeutic regimens, that target immune checkpoints, demonstrated significant antitumor response by increasing intra-tumoral immune cell populations, including CD8+ effector T cells. However, administration of such immune checkpoint inhibitors is largely inefficacious in inducing immunogenicity and treating breast cancer. Currently, there is a great need to better understand cell autonomous mechanisms of immune evasion in breast cancer to identify upstream therapeutic targets that increase the efficacy of immunotherapy. Here we show that Crk, an SH2 and SH3 domain-containing adaptor protein implicated in focal adhesion signaling, cell migration, and invasion, and frequently up-regulated in human cancers, has an important role in regulating the tumor immune microenvironment. Using a murine 4T1 breast adenocarcinoma model of spontaneous metastasis in immune-competent BALB/C mice, we show that genetic ablation of Crk by CRISPR-Cas9 leads to enhanced anti-tumor immune cell populations, cytotoxic effector and immune surveillance cytokines in primary tumor. Pathologically, this leads to a significant redu...Continue Reading

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Citations

May 31, 2018·Breast Cancer Research and Treatment·Jing LiuJian Yin
Dec 29, 2019·Science China. Life Sciences·Zijun ZhaoYan Nie
Feb 3, 2020·Cellular and Molecular Life Sciences : CMLS·Reza MohammadinejadIman Azimi
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Sep 11, 2020·Biomedicines·Chin-King LooiChun-Wai Mai
Apr 4, 2021·International Journal of Molecular Sciences·Ryuhjin Ahn, Josie Ursini-Siegel
Aug 14, 2021·Technology in Cancer Research & Treatment·Wang LiLi Haisha

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Methods Mentioned

BETA
GTPases
transfection
PCR
flow cytometry
xenograft
gene knockout
profiler

Software Mentioned

Nanostring
RT 2 Profiler PCR array
Nanostring analysis
FlowJo
[UNK] Analysis
Aperio

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