DNA methylation predicts response to Immune Checkpoint Blockade in lung cancer

Isabel Barragan | Mar 2019 | |

Isabel Barragan
Senior Researcher,
Marie Skłodowska-Curie,
Group of Pharmacoepigenetcs,
Department of Physiology and Pharmacology,
Karolinska Institutet, Stockholm

Qingyang Xiao
Group Leader, PhD student,
Group of Pharmacoepigenetics,
Department of Physiology
and Pharmacology,
Karolinska Institutet, Stockholm

Modulating immune inhibitory pathways has been a major recent breakthrough in cancer treatment. Checkpoint blockade antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programed cell-death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) have demonstrated acceptable toxicity, promising clinical responses, durable disease control, and improved survival in 20-30% of patients with advanced melanoma, and non-small cell lung cancer (NSCLC).1  However, there is a need for the identification of biomarkers that may predict response or are modulated during the course of immune-based therapy. Biomarkers predictive of response: an urgent need in the field The majority of the tested biomarkers are based on immunohistochemistry for protein detection or flow cytometry analysis for identification of the relevant cell populations.2 However, a few whole-exome -sequencing studies in tumor sections have revealed that the mutational burden sensitizes to PD-1 blockade in NSCLC, and that this burden can be originated by somatic genetic mutations in the mismatch repair genes.3 In addition, a recent study has identified a 13-gene profile that discriminated the progressing metastatic melanoma lesions during anti-PD-1 therapy.4 Not only restricted to tumor cells, but also in the tumor environment, epigenetic variations represent promising biomarkers of the immune activity that can modulate the response to antiPD-1/PD-L1/CTLA4 therapies.5 The recent “omics revolution” provides then great opportunities to elucidate the biological processes linked to the treatment outcome. In the recent -paper “Epigenetic prediction of response to anti-PD-1 treat-ment in non-small-cell lung cancer: a multi-centre, retrospective analysis” (Lancet Respir Med. 2018) we report for the first time an epigenome profile associated with the response to Immune Checkpoint Blockade (ICB), that was further simplified into a single DNA methylation marker for prediction of clinical benefit to ICB. Study design This was a multicenter, retrospective study in which 15 different hospitals in France, Spain, and Italy were involved, to recruit a total of...