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Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. (Johan Botling)
Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden;Natl Bioinformat Infrastruct Sweden, Sci Life Lab, Solna, Sweden.
Epistat, Uppsala, Sweden.
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2018 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 7, p. 1741-1752Article in journal (Refereed) Published
Abstract [en]

Tumor-associated macrophages (TAMs) are attractive targets for immunotherapy. Recently, studies in animal models showed that treatment with an anti-TAM antibody directed against the scavenger receptor MARCO resulted in suppression of tumor growth and metastatic dissemination. Here we investigated the expression of MARCO in relation to other macrophage markers and immune pathways in a non-small cell lung cancer (NSCLC) cohort (n=352). MARCO, CD68, CD163, MSR1 and programmed death ligand-1 (PD-L1) were analyzed by immunohistochemistry and immunofluorescence, and associations to other immune cells and regulatory pathways were studied in a subset of cases (n=199) with available RNA-seq data. We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a protumor phenotype. Correlation to clinical data only showed a weak trend toward worse survival for patients with high macrophage infiltration. Interestingly, MARCO was expressed on a distinct subpopulation of TAMs, which tended to aggregate in close proximity to tumor cell nests. On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules. Indeed, a higher macrophage infiltration was seen in tumors expressing PD-L1, and macrophages residing within tumor cell nests co-expressed MARCO and PD-L1. Thus, MARCO is a potential new immune target for anti-TAM treatment in a subset of NSCLC patients, possibly in combination with available immune checkpoint inhibitors.

Place, publisher, year, edition, pages
WILEY , 2018. Vol. 143, no 7, p. 1741-1752
Keywords [en]
lung cancer, MARCO, tumor-associated macrophages, immune therapy, PD-L1
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
URN: urn:nbn:se:uu:diva-364230DOI: 10.1002/ijc.31545ISI: 000443392100020PubMedID: 29667169OAI: oai:DiVA.org:uu-364230DiVA, id: diva2:1258467
Funder
Swedish Cancer SocietyAvailable from: 2018-10-24 Created: 2018-10-24 Last updated: 2019-08-20Bibliographically approved
In thesis
1. Mutation and immune profiling of non-small cell lung cancer
Open this publication in new window or tab >>Mutation and immune profiling of non-small cell lung cancer
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Several novel therapies that target molecular alterations and immune checkpoints in lung cancer have been introduced in the last decade. Still, only a minority of patients obtain long term disease control and overall survival remains poor. The aim of this thesis was to characterize the landscape of genetic alterations and immune cell infiltrates in tumor tissues from a large representative patient cohort of non-small cell lung cancer (NSCLC).

The mutational status of 82 genes related to lung cancer development were evaluated, in paper I, by a targeted re-sequencing approach adapted to work on “real-life” samples of mixed quality. We observed a remarkably high prevalence of activating KRAS mutations. Otherwise, the mutation spectrum resembled other western lung cancer populations. Poor survival was linked to subgroups of lung adenocarcinoma with mutations in TP53, STK11 and SMARCA4, independent of concomitant KRAS mutations. In lung squamous cell carcinoma, patients with mutations in CSMD3 had better survival.

The infiltration of tumor-associated immune cells was assessed by immunohistochemical analysis in paper II. Previously described immune response patterns termed “inflamed” and “desert” were confirmed in our dataset. In addition, we discovered a new immune phenotype characterized by overall sparse presence of most immune cell types except for a distinct infiltration of NK and plasma cells. This novel immune class displayed a favorable prognosis and was therefore designated “oasis”.

In paper III, infiltration of macrophage subtypes was evaluated by immunohistochemical analysis of CD68, CD163, MSR1 and MARCO. The majority of macrophages exhibited a tumor promoting phenotype and expression of MARCO, a targetable scavenger receptor, was detected in a distinct subset of NSCLC patients. Further investigation of the functional roles of MARCO in a human NSCLC setting was carried out in paper IV. Here, MARCO expression on cultured myeloid cells could be induced by NSCLC cell lines. The MARCO+ cells displayed an immunosuppressive phenotype and could effectively suppress the cytolytic effect of NK cells and CD8+ T cells. A monoclonal antibody targeting MARCO removed these inhibitory effects of the MARCO+ cells.

In summary, this thesis contributes knowledge on the genetic and immunologic underpinning of lung cancer that forms the basis for current and future treatment strategies in the evolving era of personalized oncology and pathology.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 69
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1592
Keywords
Non-small cell lung cancer, Tumor microenvironment, Tumor-associated macrophages, Immune infiltrates, PD-L1, Mutation patterns, Immune therapy, MARCO, TP53, STK11, KRAS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-390321 (URN)978-91-513-0733-6 (ISBN)
Public defence
2019-10-11, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
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Supervisors
Available from: 2019-09-19 Created: 2019-08-20 Last updated: 2019-10-15

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La Fleur, LinneaMattsson, Johanna Sofia MargaretaDjureinovic, DijanaBrandén, EvaKoyi, HirshMicke, PatrickBotling, Johan

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La Fleur, LinneaMattsson, Johanna Sofia MargaretaDjureinovic, DijanaBrunnström, HansIsaksson, JohanBrandén, EvaKoyi, HirshMicke, PatrickBotling, Johan
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Clinical and experimental pathologyScience for Life Laboratory, SciLifeLabDepartment of Immunology, Genetics and PathologyCentre for Research and Development, Gävleborg
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