Blocking PD-1/PD-L1 Axis is Required for Prolonged Response to Trametinib in Tongue and Lip Cancer Models in Mice

M Elkabets, M Parsad, S Jagadeeshan, D Friedmann-Morvibski, M Scaltriti

Research output: Contribution to journalMeeting Abstractpeer-review

Abstract

Background
Acquisition of resistance to anticancer therapies is associated with increased expression of immunosuppressor modulators that enable tumor cells to escape from the antitumor immunity machinery.

Objective
To understand the mechanisms of immune escape from MEK inhibitors in head and neck cancer (HNC).

Methods
We have developed several mitogen-activated protein kinase (MAPK) pathway-driven cancers in immunocompetent mice. Specifically, a 4NQO (tobacco surrogate) carcinogenesis induced HNC model, novel KRASG12-driven HNC model using CRISPR technology, and HRASV12 model using a lentiviral vector. These models were used to study mechanisms of immune escape from trametinib, an MAPK pathway inhibitor.

Results
All of these HNC models are sensitive to trametinib in vitro and in vivo; however, over time, resistance was developed, and tumor progression was detected. In this work, we found that chronic treatment with trametinib induced epithelial-mesenchymal transition and upregulation of the tumor-derived immunosuppressor modulators like PD-L1. The tumor ecosystem was also altered during the acquisition of resistance because upon short treatment with trametininb during stable disease, tumors were enriched with infiltrated CD8+ T, whereas upon progression the CD8+ T cells in the tumors showed an exhausted phenotype with high levels of programmed cell death protein 1 (PD-1). Blocking the immune escape mechanisms using anti PD-1/ programmed death ligand 1 (PD-L1) drugs together with trametinib induced tumor eradication and most mice were cured.

Conclusions
Our findings suggest that administration of blockers of the PD1/PD-L1 axis enhance the antitumor activity of MAPK-targeted drugs and delay the appearance of resistance.
Original languageEnglish GB
Pages (from-to)e16
JournalOral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Volume132
Issue number1
StatePublished - 2021

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