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E. Aldeguer
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-015 - Interferon-Gamma (INFG) as a Biomarker to Guide Immune Checkpoint Blockade (ICB) in Cancer Therapy (ID 8939)
09:30 - 09:30 | Author(s): E. Aldeguer
- Abstract
Background:
PD-L1 is induced by oncogenic signals or via INFG. STAT3, through DNMT1, epigenetically silences STAT1 and RIG-I and opposes INFG signaling. TET1 is a DNA demethylase. I kappa B kinase epsilon (IKBKE), a noncanonical I-kappa-B kinase, is essential for INFG induction, but can also promote NFATc1 phosphorylation and T cell response inhibition. Eomesodermin (Eomes) regulates T cell exhaustion. CCL5 (or Rantes), dependent on STAT3, causes myeloid-derived suppressor cell (MDSC) recruitment. YAP1 can also drive MDSC recruitment via CXCL5 signaling. We have explored whether the expression of genes related to INFG signaling, T cell exhaustion and MDSC recruitment is associated with response to ICB.
Method:
Total RNA from pre-treatment tissue samples of 17 NSCLC and 21 melanoma patients treated with nivolumab and pembrolizumab respectively, was analyzed by qRT-PCR. INFG, STAT3, IKBKE, STAT1, RIG-I and PD-L1 mRNA were examined. CCL5, YAP1, CXCL5, NFATC1, EOMES and TET1 expression was additionally assessed. Gene expression was categorized with respect to tertiles and patients were divided into two risk groups (low and intermediate/high). CD8[+ ]tumor-infiltrating lymphocytes (TILs) and PD-L1 protein expression in tumor and CD8[+ ]TILs were examined by immunohistochemistry (SP57 and SP142 assay, respectively). Progression free survival (PFS), overall survival (OS) and Disease Control Rate (DCR) were estimated.
Result:
Seventeen NSCLC patients, previously treated with one or more prior systemic therapies, received nivolumab. IKBKE was positively correlated with INFG (r=0.65, p=0.0124) and PD-L1 (r=0.58, p=0.0225) expression. RIG-I was loosely anticorrelated with NFATc1 (r=-0.55, p=0.0518). Among all biomarkers explored, only INFG was associated with PFS, OS and DCR. Specifically, PFS was significantly longer for nivolumab-treated patients with intermediate/high versus low INFG expression (5.1 versus 2.0 months, p=0.0124). OS was longer (though not statistically significant) for patients with intermediate/high versus low INFG expression (10.2 versus 4.9 months, p=0.0687). DCR to nivolumab was 71.43% for patients with intermediate/high INFG versus 0% for patients with low INFG expression. Neither PD-L1 immunohistochemistry expression nor CD8[+ ]TILs were related to nivolumab outcome. The same results were observed for 21 melanoma patients treated with pembrolizumab.
Conclusion:
IFNG production by T-cells plays critical roles in anti-cancer immune responses by augmentation of MHC Class I expression, growth arrest, post-proteasomal trimming of antigen epitopes, recruitment of effector cells, induction of T-regs fragility and PD-L1 expression. Further research is warranted in order to validate whether INFG is more accurate than PD-L1.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-034 - PD-L1 Expression Can Be a Prognostic Marker in EGFR Mutant NSCLC Patients Treated with Erlotinib (ID 8933)
09:30 - 09:30 | Author(s): E. Aldeguer
- Abstract
Background:
INF-gamma secreted by CD8+ lymphocytes upregulates PD-L1 expression in cancer cells. We recently identified STAT3 and YAP1 as compensatory mechanisms of resistance to EGFR tyrosine kinase inhibition in EGFR mutant cells. STAT3 and YAP1 up-regulate CCL5 (Rantes) and CXCL5, respectively, with both chemokines attracting the myeloid-derived suppressor cell. STAT3 stimulates DNMT1 by repressing STAT1 and retinoic acid-inducible gene-I (RIG-I) expression. STAT1 and RIG-I are key mediators in INF-gamma signaling. We assume that alterations in the INF-gamma signaling pathway could be present in EGFR mutant NSCLC.
Method:
Total RNA from 53 EGFR mutant NSCLC patients was reversed transcribed and analyzed by qRT-PCR. STAT3, YAP1, RIG-I, STAT1, PD-L1, DNMT1 and CXCL5 mRNA were examined with specific primers/probes in triplicates. Progression-free survival (PFS) and overall survival (OS) were estimated.
Result:
Fifty-three EGFR mutant NSCLC patients treated with erlotinib were analyzed, 72% were female, 62% never-smoked, 70% had exon 19 deletion and 36% brain metastases. A positive correlation was found between RIG-1 and STAT1 (r=0.42, p=0.003). An anti-correlation trend was noted between STAT3 and PD-L1, YAP1 and PD-L1 and DNMT1 and STAT1. Median PFS was 22, 12.9 and 8.6 months for patients with high, intermediate and low PD-L1 mRNA, respectively (P=0.04). Median PFS was numerically longer for patients with low levels of DNMT1, RIG1 STAT1 and CXCL5, although the differences were not statistically significant. A similar trend was observed for OS.
Conclusion:
PD-L1 mRNA could be a prognostic marker in EGFR mutant NSCLC patients. Down-modulation of PD-L1 indicates alterations in pattern-recognition receptors (PRRs), like RIG-1 or downstream interferon signaling factors. The dysregualtion of the pathway is multifactorial, and the role of STAT3 and YAP1 hyperactivation merits further research. DNMT1 overexpression ablates STAT1. Since the cyclin-dependent kinase 4 (CDK4) interacts with DNMT1, therapies with CDK4 inhibitors can directly neutralize the main defects in the INF-gamma signaling pathway.
