Elsevier

Journal of Thoracic Oncology

Volume 15, Issue 9, September 2020, Pages 1507-1521
Journal of Thoracic Oncology

Original Article
Small Cell Lung Cancer
Harnessing Natural Killer Immunity in Metastatic SCLC

https://doi.org/10.1016/j.jtho.2020.05.008Get rights and content
Under a Creative Commons license
open access

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

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

Cited by (0)

Dr. Best and Mr. Hess contributed equally to this work.

Disclosure: Drs. Huntington and Rautela are cofounders and Drs. Cursons, Rautela, and Huntington are shareholders of oNKo-Innate Pty Ltd.