Harnessing Natural Killer Immunity in Metastatic SCLC

Sarah A Best; Jonas B Hess; Fernando Souza-Fonseca-Guimaraes; Joseph Cursons; Ariena Kersbergen; Xueyi Dong; Jai Rautela; Stephanie R Hyslop; Matthew E Ritchie; Melissa J Davis; Tracy L Leong; Louis Irving; Daniel Steinfort; Nicholas D Huntington; Kate D Sutherland

doi:10.1016/j.jtho.2020.05.008

Harnessing Natural Killer Immunity in Metastatic SCLC

J Thorac Oncol. 2020 Sep;15(9):1507-1521. doi: 10.1016/j.jtho.2020.05.008. Epub 2020 May 26.

Authors

Affiliations

¹ ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
² University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia; Translational Research Institute, Brisbane, Queensland, Australia; Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
³ Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
⁴ ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
⁵ Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
⁶ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
⁷ Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, Australia.
⁸ Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
⁹ Department of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Respiratory and Sleep Medicine, Austin Hospital, Heidelberg, Victoria, Australia; Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
¹⁰ Department of Medicine, University of Melbourne, Parkville, Victoria, Australia; Department of Respiratory Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
¹¹ Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
¹² ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: [email protected].

PMID: 32470639
DOI: 10.1016/j.jtho.2020.05.008

Abstract

Introduction: SCLC is the most aggressive subtype of lung cancer, and though most patients initially respond to platinum-based chemotherapy, resistance develops rapidly. Immunotherapy holds promise in the treatment of lung cancer; however, patients with SCLC exhibit poor overall responses highlighting the necessity for alternative approaches. Natural killer (NK) cells are an alternative to T cell-based immunotherapies that do not require sensitization to antigens presented on the surface of tumor cells.

Methods: We investigated the immunophenotype of human SCLC tumors by both flow cytometry on fresh samples and bioinformatic analysis. Cell lines generated from murine SCLC were transplanted into mice lacking key cytotoxic immune cells. Subcutaneous tumor growth, metastatic dissemination, and activation of CD8⁺ T and NK cells were evaluated by histology and flow cytometry.

Results: Transcriptomic analysis of human SCLC tumors revealed heterogeneous immune checkpoint and cytotoxic signature profiles. Using sophisticated, genetically engineered mouse models, we reported that the absence of NK cells, but not CD8⁺ T cells, substantially enhanced metastatic dissemination of SCLC tumor cells in vivo. Moreover, hyperactivation of NK cell activity through augmentation of interleukin-15 or transforming growth factor-β signaling pathways ameliorated SCLC metastases, an effect that was enhanced when combined with antiprogrammed cell death-1 therapy.

Conclusions: These proof-of-principle findings provide a rationale for exploiting the antitumor functions of NK cells in the treatment of patients with SCLC. Moreover, the distinct immune profiles of SCLC subtypes reveal an unappreciated level of heterogeneity that warrants further investigation in the stratification of patients for immunotherapy.

Keywords: GEMMs; Genetically engineered mouse models; Metastasis; NK; Natural killer cells; PD-1; Programmed cell death-protein 1; SCLC; Small cell lung cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Immunotherapy
Killer Cells, Natural
Lung Neoplasms*
Mice
T-Lymphocytes