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Peng Cao
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FP03 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) (ID 151)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP03.04 - Selinexor can Inhibit Nuclear Export of HMGB1, a Negative Predictive Marker for Immunotherapy Response (ID 3616)
00:00 - 00:00 | Author(s): Peng Cao
- Abstract
- Presentation
Introduction
The high mobility group box 1 (HMGB1) normally acts as a DNA chaperone in the nucleus, but was previously shown to be involved in various inflammatory diseases and cancer. Endogenous stimuli and oxidative stress can induce the transport of HMGB1 from the nucleus to the cytoplasm through exportin 1 (XPO1/CRM1). In addition, XPO1 was shown to be responsible for nuclear transport of HIV-1. Consequent release of HMGB1 from the cell as a damage-associated molecular pattern (DAMP) was found to have a paradoxical role in cell survival and death, by either activating an immune response through TLRs and RAGE receptors, or by inhibition of the immune response through CD24 and TIM-3 receptors. Selinexor (KPT-330) is an FDA-approved XPO1 inhibitor that prevents the release of HMGB1 from the nucleus to the cytoplasm. Selinexor was previously shown to be effective in KRAS mutant lung adenocarcinoma cell lines. We hypothesized that HMGB1 and XPO1 may be important biomarkers in cancer patients that will receive immune checkpoint inhibitors (ICIs).
Methods
Pre-ICI-treatment FFPE tumor tissue samples from 15 HIV-infected and 30 non-HIV-infected cancer patients, mainly lung cancer, were analyzed using the nCounter NanoString platform with the Human PanCancer IO360 panel. The IO360 panel can be used to analyze the expression of 770 genes related to tumor biology, immune response and microenvironment. HMGB1 mRNA expression results were correlated with HIV status and clinical benefit (CB; objective response or stable disease of more than 24 weeks by RECIST1.1 criteria). Next, XPO1 was inhibited in lung cancer cell lines using selinexor and integrase inhibitors (INSTIs) and effects on cell viability and nuclear export of HMGB1 were evaluated. Moreover, combination therapies using selinexor and EGFR or MET inhibitors were tested and effects on cell viability were determined.
Results
HMGB1 mRNA expression was lower in patients that had CB from ICI treatment (p = 0.04). No significant differences were found in HMGB1 mRNA expression between patients with- and without HIV-1 infections. Kaplan Meier analysis revealed that patients with lower HMGB1 mRNA expression have better overall survival, both in our patient cohort (p = 0.004), and a TCGA lung adenocarcinoma patient cohort (p = 0.003). Inhibition of the HMGB1 transporter, using either selinexor or INSTIs, can prevent nuclear export of HMGB1 in the PC9 lung cancer cell line and inhibit cell proliferation in EGFR and KRAS mutant cell lines. Combination treatments with selinexor decreased cell viability in lung cancer cell lines when compared to single treatment.
Conclusion
In this study we found HMGB1 mRNA to be lower expressed in tumor tissue of pre-ICI-treated cancer patients with clinical benefit from treatment, indicating that HMGB1 expression may be used as a negative predictive marker for immunotherapy response. Further exploration should focus on validating this finding in a larger patient cohort and future in vivo studies should reveal if the combination of ICIs and XPO1 inhibitors could yield better responses to immunotherapy. Therefore, HMGB1 may be used to predict clinical benefit from ICI treatment and provides a new target for cancer treatment.
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