Exth-12. Radiation Enhances Melanoma Response to Immunotherapy and Synergizes With Benzodiazepines to Promote Anti-Tumor Activity

Abstract

Melanoma brain metastases (MBM) occur in ~50% of advanced melanoma patients. It is unclear if systemic therapies synergize with radiotherapy (RT) and what the impact of RT timing has on efficacy. We find that RT followed by ICI (immune checkpoint inhibitors) (RTàICI) improves MBM patient survival compared to other combination strategies, also shown here in a murine melanoma model. RNA-seq of MBM tumors in the RTàICI group exhibit overrepresentation of genes implicated in NFKB signaling. There is also expression of GABAA receptor subunits across both treatment groups. We show that melanoma cells express functional GABAA receptors and that benzodiazepines impair tumor growth. Combination of sub-lethal RT doses with benzodiazepine results in significant ipsilateral and out of field abscopal anti-tumor activity, which is associated with enhanced tumor infiltration with poly-functional CD8 T-cells. This study provides evidence that RT enhances MBM response to ICI and synergizes with benzodiazepines to promote anti-tumor activity.

Conserved pan-cancer microenvironment subtypes predict response to immunotherapy

“…A.B., F.F., N.K., and R.A. are inventors on patents related to the TME classification platform and the visual tool. RNA-seq expression for cohorts where raw fastq files were available: Auslander (GSE115821) (Auslander et al, 2018); Badal (GSE98394) (Badal et al, 2017); Gide (ERP105482) (Gide et al, 2019); Hugo (GSE78220, GSE96619) (Hugo et al, 2016;Garcia-Diaz et al, 2017); Khan (GSE131521) (Pomeranz Krummel et al, 2019), Kunz (GSE112509) (Kunz et al, 2018), Liang (phs001036) (Liang et al, 2017), Nathanson (SRP067586) (Nathanson et al, 2017), Riaz (GSE91061) (Riaz et al, 2017), TCGA-SKCM (Cancer Genome Atlas Network, 2015), Van Allen (phs000452) (Van Allen et al, 2015;Liu et al, 2019a) was re-calculated using a unified RNA-seq pipeline (Vivian et al, 2017; https://xenabrowser.net/). Cohorts with the same RNA extraction type, sample source and similar sequencing protocols were combined into large cohort groups and processed together controlling for batch effects in the space of the Fges (Figure S13).…”

“…The Auslander et al cohort (Auslander et al, 2018) was excluded due to low patient number and the high prevalence of nonresponders. The GSE131521 (Pomeranz Krummel et al, 2019) cohort was excluded because it primarily consisted of brain metastases and almost completely was classified as TME subtype D. The Liang et al cohort (Liang et al, 2017) was excluded due to all samples being acral melanomas. Finally, the Gide, Liu, Hugo cohort samples were combined and analyzed as shown in Figure S13 (Table S5).…”

“…Accessions for the datasets used in this study include the following: phs000178 (TCGA), GSE2109 (adenocarcinomas), GSE65904 (Cirenajwis et al, 2015), GSE59455 (Budden et al, 2016), GSE98394 (Badal et al, 2017), phs001036 (Liang et al, 2017), GSE91061 (Riaz et al, 2017), GSE43081 (Hao et al, 2017), ERP105482 (Gide et al, 2019), GSE54467 and GSE80435 (AJCC_1 and AJCC_2 (Hayward et al, 2017;Jayawardana et al, 2015), GSE8401 (Xu et al, 2008), GSE112509 (Kunz et al, 2018), GSE35640 (Ulloa- Montoya et al, 2013), GSE15605 (Raskin et al, 2013), GSE22153 (Jo ¨nsson et al, 2010, GSE19293 (Augustine et al, 2010), GSE19234 (Bogunovic et al, 2009), phs000452 (Liu et al, 2019a;Van Allen et al, 2015), GSE115821 (Auslander et al, 2018), GSE78220 and GSE96619 (Hugo et al, 2016;Garcia-Diaz et al, 2017), GSE100797 (Lauss et al, 2017), SRP067586 (Nathanson et al, 2017), GSE131521/SRP198996 (Pomeranz Krummel et al, 2019), EGAS00001002556 (Mariathasan et al, 2018), GSE135222 (Jung et al, 2019), ENA: ERP107734/SRA: PRJEB25780 (Kim et al, 2018).…”