NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control

Jan P Böttcher,Eduardo Bonavita,Probir Chakravarty,Hanna Blees,Mar Cabeza-Cabrerizo,Stefano Sammicheli,Neil C Rogers,Erik Sahai,Santiago Zelenay,Caetano Reis E Sousa

doi:10.1016/j.cell.2018.01.004

Jan P Böttcher, Eduardo Bonavita + Show 8 more

Open Access

https://doi.org/10.1016/j.cell.2018.01.004

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Journal: Cell	Publication Date: Feb 1, 2018
Citations: 1232	License type: cc-by

Affiliation: The Francis Crick Institute, University of Manchester

Abstract

SummaryConventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE2) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE2 for immune evasion and that could be exploited for cancer therapy.

Highlights

The tumor microenvironment (TME) contains stromal cells and immune cells that shape cancer development and impact the response to tumor therapy (Hanahan and Weinberg, 2011; Palucka and Coussens, 2016)
We extended the analysis to other mouse cancer models and found that, similar to BRAFV600E melanoma, tumors formed by COX-competent but not COX-deficient CT26 colorectal cancer cells or 4T1 breast cancer cells displayed low numbers of intratumoral cDC1 (Figures S1A–S1D)
We found that in vivo blockade of CCL5 and XCL1 resulted in markedly reduced cDC1 accumulation within tumors (Figure 5B)

Summary

Introduction

The tumor microenvironment (TME) contains stromal cells and immune cells that shape cancer development and impact the response to tumor therapy (Hanahan and Weinberg, 2011; Palucka and Coussens, 2016). Intratumoral immune cells comprise lymphocytes, such as T cells, B, cells and natural killer (NK) cells, and diverse populations of myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells (DCs) (Gajewski et al, 2013; Hanahan and Weinberg, 2011; Palucka and Coussens, 2016). Intratumoral monocytes and M2-polarized macrophages can promote cancer cell growth, angiogenesis, and metastasis, as well as contribute to the establishment of an immunosuppressive environment. They are associated with tumor progression and poor clinical outcome (Noy and Pollard, 2014). M1-polarized macrophages and DCs contribute to anti-tumor immunity and are associated with a favorable outcome (Engblom et al, 2016)

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