83P - Aberrant spliceosome kinetics and structural variations drive the production of soluble PD-L1 mRNA in various cancer and immune cell types. (83P)

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Diagnostics
Bioethics, Legal, and Economic Issues
Presenter Spyros Papamichos
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors S.I. Papamichos, I. Kotsianidis
  • Department Of Haematology, Democritus University of Thrace Medical School, 68131 - Alexandroupolis/GR

Abstract

Background

Release of biologically active soluble PD-L1 (sPD-L1) from tumor cells has been causally linked to aggressive pathologic features. Current data support that sPD-L1 is released through proteolytic cleavage of the membrane-bound protein.

Methods

CD274 genomic sequence and corresponding expressed sequence tag (EST) data were downloaded from the National Center for Biotechnology Information (NCBI) portal. CD274 sequence was scanned for the presence of integrated transposable elements by RepeatMasker software. CD274 high-throughput sequencing of polyadenylated RNA (RNA-Seq) data in several normal somatic tissues were analyzed via the NCBI and GTEx Portals. CD274 ribosome profiling data across various cancer tissues were analyzed via the GWIPS‐viz Portal.

Results

CD274 alternatively spliced variant 4 (v4), only recently annotated from NCBI (NM_001314029), represents an aberrant mRNA which was evolutionarily derived from the “exaptation” of an L2a retrotransposon. The truncated peptide encoded by CD274 v4 comprises exclusively PD-L1 extracellular domains and is likely to subsist in soluble form. Expression data of CD274 v4 are scarce in normal somatic tissues, indicating the rarity of its expression under normal conditions. Vice versa, various ESTs support the expression of CD274 v4 in ovarian cancer. Furthermore, ribosome-protected fragments of CD274 v4 are present in breast cancer, cervical cancer, and osteosarcoma cells as well as in TLR2-stimulated macrophages. Recently, Kataoka et al. (Nature, 2016) interrogated 10,210 cancer samples for structural variations (SVs) converging on CD274 3'-untranslated region (3'-UTR). Whilst not reported, in 11 of the 31 SV(+) samples identified, the aberrant transcripts detected are likely to encode for soluble PD-L1 isoforms.

Conclusions

Either generated via retrotransposon “exaptation” or produced via 3'-UTR SVs, aberrant CD274 transcripts are likely to directly encode for sPD-L1 in various cancer cell types and activated immune cells. Whether quantification of these transcripts via PCR-based assays could be efficiently used in predicting sensitivity to treatment with immune checkpoint inhibitors represents an intriguing question.

Clinical trial identification

Legal entity responsible for the study

Spyros I. Papamichos

Funding

None

Disclosure

All authors have declared no conflicts of interest.