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Theranostics 2018; 8(21):5842-5854. doi:10.7150/thno.26888 This issue Cite

Research Paper

Arg1 expression defines immunosuppressive subsets of tumor-associated macrophages

Sean P. Arlauckas^1*, Seth B. Garren^1*, Chris S. Garris¹, Rainer H. Kohler¹, Juhyun Oh¹, Mikael J. Pittet¹, Ralph Weissleder^{1,2 ✉}

1. Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114,
2. Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115
* equal contribution

✉ Corresponding author: R. Weissleder, MD, PhD. Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA, 02114. 617-726-8226 rweisslederharvard.edu

Abstract

Tumor-associated macrophages (TAM) have attracted attention as they can modulate key cancer-related activities, yet TAM represent a heterogenous group of cells that remain incompletely characterized. In growing tumors, TAM are often referred to as M2-like macrophages, which are cells that display immunosuppressive and tumorigenic functions and express the enzyme arginase 1 (Arg1).

Methods: Here we combined high resolution intravital imaging with single cell RNA seq to uncover the topography and molecular profiles of immunosuppressive macrophages in mice. We further assessed how immunotherapeutic interventions impact these cells directly in vivo.

Results: We show that: i) Arg1+ macrophages are more abundant in tumors compared to other organs; ii) there exist two morphologically distinct subsets of Arg1 TAM defined by previously unknown markers (Gbp2b, Bst1, Sgk1, Pmepa1, Ms4a7); iii) anti-Programmed Cell Death-1 (aPD-1) therapy decreases the number of Arg1+ TAM while increasing Arg1- TAM; iv) accordingly, pharmacological inhibition of arginase 1 does not synergize with aPD-1 therapy.

Conclusion: Overall, this research shows how powerful complementary single cell analytical approaches can be used to improve our understanding of drug action in vivo.

Keywords: immunotherapy, cancer, PD1, macrophage, arginase

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