Background Immune checkpoint inhibitors (ICIs) have inferior clinical response in patients with oncogene-driven lung adenocarcinoma (LUAD). There is also an unmet need for patients with non-oncogene-driven LUAD who failed first line ICI-containing treatment. Labyrinthin (LAB) is a novel cancer neoantigen expressed on the surface of adenocarcinoma cells of various cancer types including LUAD. We recently showed that LAB was expressed in LUAD by immunohistochemistry and is an independent prognostic factor for LUAD. The objective of this study was to determine if LAB is a target in different LUAD subgroups.
Methods LAB mRNA expression was assessed in The Cancer Genome Atlas (TCGA) LUAD dataset. LAB-specific mRNA expression was determined by averaging expression of exons specific to LAB and not the related splice variant aspartyl/asparaginyl beta-hydroxylase (ASPH). Patients with tyrosine-kinase inhibitor (TKI)-sensitive driver oncogenes were defined as those with an FDA-approved targeted therapy (e.g., mutations in EGFR, BRAF V600E, MET E14SP, ERBB2 and gene fusions in ALK, ROS1 and RET). Patients with other oncogenes included other BRAF mutations, KRAS, HRAS, NRAS and MAP2K).The results are validated in an independent cohort of clinically annotated patients with LUAD.
Results As expected, TKI-sensitive oncogene-driven LUAD (n=54) had statistically lower tumor mutational burden (TMB) (2.8 mut/MB, p<0.001) compared to other oncogene-driven LUAD (n=89,7.0 mut/MB) and non-oncogene-driven LUAD (n=87, 9.2 mut/MB), which is associated with poor response to ICIs. LAB RNA expression was higher in primary tumors than normal tissue specimens across different subgroups of TCGA-LUAD (figure 1). Furthermore, LAB expression was found to positively correlate with PD-L1 mRNA expression across these LUAD subgroups. RNA sequencing analysis of blood mononuclear cells of two pts enrolled in phase I trial revealed that LabVax 3(22)-23 and adjuvant GM-CSF treatment modulated the activity of immune cells and PD-1 pathway.
Conclusions LAB is a promising cancer neoantigen for both oncogene-driven and non-oncogene-driven LUAD, which warrant further study.
Acknowledgements This research was supported by the Personalized Cancer Therapy Gift Fund and Novel Treatment Strat for Adenocarcinoma (T.L.), and the Biostatistics Shared Resource funded by the UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (NCI P30CA093373) (S.C.).
Ethics Approval UCD IRB#937274.Biomarkers for Patients with Advanced Solid Tumors. Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
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