Abstract 688P
Background
Several data indicate that Poly-Adenosine diphosphate-Ribose Polymerase inhibitors (PARPi) promote immunomodulatory changes. In a phase II window study of Olaparib alone or with Cisplatin or with Durvalumab or no treatment, we performed transcriptomic profiling to evaluate the modulation of tumor microenvironment post- treatment.
Methods
Pre- and post-treatment FFPE whole tissue sections from 30 HNSCC patients, enrolled in phase II trial OPHELIA, (olaparib alone, n = 9; cisplatin plus olaparib, n = 12; durvalumab plus olaparib, n = 9), were employed. The mRNA transcripts were hybridized to 4-color-coded tags, specific for each of the targets included in the 770-plex PanCancer IO360 panel (NanoString), measured on the nCounter platform. Pre- and post-treatment CD163 and CSF1R were also assessed using quantitative immunofluorescence (QIF) in three patients, with the highest differential expression in the corresponding transcripts. P-values were adjusted using the False Discovery Rate (FDR) adjustment.
Results
PARP inhibitor therapy modulates the TME in HNSCC and results in increased levels of intratumoral macrophages. Transcripts associated with macrophage including CD163, Colony Stimulating Factor 1 Receptor (CSF1R), CD14 and co-stimulatory molecule TNFSF4 (OX40L) were significantly upregulated post-treatment (P adjust <0.05). Genes involved in antigen presentation (HLA-DMA), chemokine- and cytokine-signaling cascades (CCL14, CXCL12, CXCR4) and Toll- like receptors (TLR4) were also upregulated, suggesting aberrant myeloid activity. Olaparib- based treatment resulted in a significant increase in genes involved in angiogenesis (PDGFRB, VEGFB, COL11A1) (Padjust<0.05). Furthermore, we observed increases in transcripts among genes related to pro-inflammatory cytokine signaling (IL32), lymphocytes (CD4) as well as those encoding for apoptosis (BCL2) (Padjust <0.05).
Conclusions
Our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment. These results are consistent with data showing that targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer.
Clinical trial identification
NCT02882308.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
AstraZeneca.
Disclosure
G. Fountzilas: Other, Personal, Honoraria: AstraZeneca. D. Rimm: Other, Personal, Advisory Role: AstraZeneca, Agendia, Amgen, BMS, Cell Signaling Technology, Cepheid, Danaher, Daiichi Sankyo, Genoptix/Novartis, GSK, Konica Minolta, Merck, NanoString, Paige.AI, Roche, Sanofi; Other, Personal, Sponsor/Funding: Amgen, Cepheid, NavigateBP, NextCure, Konica Minolta. A. Psyrri: Financial Interests, Personal, Invited Speaker: MSD, Merck Serono; Financial Interests, Personal, Advisory Board: Pfizer, Sanofi, MSD, AstraZeneca, BMS, Leo, Rakuten, eTheRNA Immunotherapies; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Iovance, Pfizer, Roche, GSK, Genesis, Incyte, Amgen, Debiopharm, MSD, Janssen, Lilly, Regeneron, Sanofi, BI, Roche, Peregrine, Oncolytics Biotech; Financial Interests, Invited Speaker: AstraZeneca, Kura Oncology; Financial Interests, Institutional, Invited Speaker: Kura Oncology, Novartis; Financial Interests, Personal and Institutional, Funding: Kura Oncology, BMS, Roche, Demo, Amgen, BI, Genesis, BMS, Pfizer, Oncolytics Biotech; Financial Interests, Institutional, Funding: Merck Serono, Pfizer; Financial Interests, Personal, Other, Educational activity: Medscape, PrimeOncology; Non-Financial Interests, Project Lead, Medical Education with honoraria: Medscape. All other authors have declared no conflicts of interest.