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Poster display session

2994 - Effect of MEK inhibition on PD-L1 and MCH-1 expression and on cytokines production profile in NSCLC cells and in human lymphocites

Date

10 Sep 2017

Session

Poster display session

Topics

Cancers in Adolescents and Young Adults (AYA);  Immunotherapy;  Thoracic Malignancies

Presenters

Carminia Maria Della Corte

Citation

Annals of Oncology (2017) 28 (suppl_5): v403-v427. 10.1093/annonc/mdx376

Authors

C.M. Della Corte1, G. Barra2, V. Ciaramella1, F. Papaccio1, G. Viscardi1, G. Esposito3, R. Di Liello1, M. Orditura4, T. Troiani5, R. De Palma2, F. Ciardiello4, F. Morgillo4

Author affiliations

  • 1 Oncology, Università degli Studi della Campania Luigi Vanvitelli, 80131 - Napoli/IT
  • 2 Immunologia Clinica, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80138 - Napoli/IT
  • 3 Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 80131 - Napoli/IT
  • 4 Dipartimento Medico-chirurgico Di Internistica Clinica E Sperimentale "f. Magrassi E A. Lanzara", Università degli Studi della Campania "Luigi Vanvitelli", 80131 - naples/IT
  • 5 Oncologia Medica, Dipartimento Di Internistica Clinica E Sperimentale “f. Magrassi”,, Università degli Studi della Campania Luigi Vanvitelli, 80131 - Napoli/IT
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Resources

Abstract 2994

Background

Understanding of cancer-immune system interaction led to development of immunotherapy; anti-programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) antibodies are now used in non small cell lung cancer (NSCLC) treatment. MAPK cascade is a key intracellular network for tumor proliferation and recent data suggest that it is implicated in interplay of tumor and T-CD8+ cytotoxic lymphocytes (CTL).

Methods

We evaluated PD-L1 mRNA level by Real Time qPCR (RT-qPCR) and its protein production, togheter with MAPK proteins, by western blot (WB), in NSCLC cell lines. Then, we studied the changes in PD-L1 and major histocompatibility complex class-I (MHC-I) expression and cytokines’ production, after MAPK-inhibition or -stimulation, by MEK-inhibitor, cobimetinib, or phorbol 12-myristate 13-acetate (PMA), respectively. In addition, we explored the effect of cobimetinib on cytokines’ genes by RT-qPCR on cDNA, obtained from retro-transcription of RNA extracted from T-lymphocytes, derived from Peripheral blood mononuclear cells (PBMC) of healthy volunteers, by density gradient separation, and activated with anti-CD3/anti-CD28 coated beads.

Results

WB and RT-qPCR for PD-L1 in NSCLC cells revealed a consistent correlation between mRNA and protein levels, togheter with activated MAPK and MEK1/2 signals, and suggested that ectopic PD-L1 mainly depends on trascriptional regulation. PDL-1 levels were significantly decreased by cobimetinib and increased by PMA, suggesting that MAPK can regulate PD-L1. Moreover, MEK-inhibition resulted on cancer cells in increased synthesis of MHC-I, IFN-gamma, IL-6, IL-1B, and TNFalpha, involved in CTL activation, and on activated human pheripheral T-lymphocytes in increment of mRNA levels of IL-12, TNFalpha and IFNgamma, that are pro-inflammatory cytokines typical of CTL subset, that seems more involved in immune response against cancer.

Conclusions

These results demonstrate that MEK-inhibion induces the establishment of a pro-inflammatory microenvironment and may represent a potential mechanism to convert otherwise resistant cancers through treatment combination strategies of MEK-inhibitors and anti-PD-L1/PD-1 antibodies in NSCLC.

Clinical trial identification

Not applicable

Legal entity responsible for the study

AOU Università della Campania “Luigi Vanvitelli”

Funding

AIRC

Disclosure

All authors have declared no conflicts of interest.

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