HMGB1 Expression Levels Correlate with Response to Immunotherapy in Non-Small Cell Lung Cancer

Abstract

Purpose

High-mobility group box 1 protein (HMGB1) is subject to exportin 1 (XPO1)-dependent nuclear export, and it is involved in functions implicated in resistance to immunotherapy. We investigated whether HMGB1 mRNA expression was associated with response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC).

Patients and Methods

RNA was isolated from pretreatment biopsies of patients with advanced NSCLC treated with ICI. Gene expression analysis of several genes, including HMGB1, was conducted using the NanoString Counter analysis system (PanCancer Immune Profiling Panel). Western blotting analysis and cell viability assays in EGFR and KRAS mutant cell lines were carried out. Evaluation of the antitumoral effect of ICI in combination with XPO1 blocker (selinexor) and trametinib was determined in a murine Lewis lung carcinoma model.

Results

HMGB1 mRNA levels in NSCLC patients treated with ICI correlated with progression-free survival (PFS) (median PFS 9.0 versus 18.0 months, P=0.008, hazard ratio=0.30 in high versus low HMGB1). After TNF-α stimulation, HMGB1 accumulates in the cytoplasm of PC9 cells, but this accumulation can be prevented by using selinexor or antiretroviral drugs. Erlotinib or osimertinib with selinexor in EGFR-mutant cells and trametinib plus selinexor in KRAS mutant abolish tumor cell proliferation. Selinexor with a PD-1 inhibitor with or without trametinib abrogates the tumor growth in the murine Lewis lung cancer model.

Conclusion

An in-depth exploration of the functions of HMGB1 mRNA and protein is expected to uncover new potential targets and provide a basis for treating metastatic NSCLC in combination with ICI.

Keywords:

• HMGB1
• immunotherapy
• non-small cell lung cancer
• Lewis lung cancer murine model
• K-Ras mutations

Data Sharing Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Acknowledgments

The investigators wish to thank the patients for kindly agreeing to donate samples to this study. We also thank all the physicians who collaborated by providing clinical information.

This work was supported by a European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement ELBA [No 765492], the National Science Foundation for Distinguished Young Scholars [82125037], the Major National Science and Technology Program of China for Innovative Drug [2017ZX09101002–002-006], and by the Key R&D Program of Jiangsu Province [BE2018755, HBZ2021-012]. This work was also partially supported by a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE) and by the Public Ministry of Labor Campinas (Research, Prevention, and Education of Occupational Cancer). This work is in memory of the generous support provided by the late Julian Santamaría Valiño to the IOR Foundation.

Disclosure

Dr Andrés Aguilar reports personal fee and/or non-financial support for congress, travel and/or speaker honoraria from MERCK SHARP and DOHME, Janssen-Cilag S.A., ROCHE-FARMA SA, TAKEDA ONCOLOGY, Bristol-Myers Squibb, outside the submitted work. The authors declare that they have no other known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.