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Project

A single-cell approach to identify biomarkers of efficacy and toxicity for immune checkpoint blockade in non-small cell lung cancer.

Immunotherapy, and specifically immune checkpoint inhibition (ICI), has revolutionized care for lung cancer patients. Despite the undeniable progress, ICI has also brought along a whole new spectrum of side effects termed immune-related adverse events (irAEs). ICI-pneumonitis is an irAE of special interest; it has a high prevalence in anti-PD-1/PD-L1 treated lung cancer patients and is the most frequent fatal irAE in this population. This largely reflects difficulties in diagnosing and treating ICI-pneumonitis, due to limited pathophysiological understanding.

In a first study, we thus performed scRNA- and scTCR-seq on bronchoalveolar lavage fluid (BALF) of ICI-pneumonitis patients and demographically matched controls. We observed T-cell enrichment in ICI-pneumonitis BALF. Most notably, we identified accumulation of pathogenic T-helper 17.1 cells. Myeloid cells were characterized by a decrease of alveolar macrophages and a relative increase of pro-inflammatory “M1-like” monocytes. We hypothesize a conserved feedforward loop drives ICI-pneumonitis, in which GM-CSF secreted by pathogenic T-helper 17.1 cells promotes tissue inflammation and IL-1/IL-23 production by pro-inflammatory monocytes and vice versa. Orthogonal validation is ongoing so that pathogenic T-helper 17.1 cells and the interplay with monocytes may be therapeutically targeted; anti-IL-23 or anti-IL-1 deserve further research in this regard, particularly given their (oncological) safety profile.

The COVID-19 pandemic further complicated management of pneumonitis in ICI-treated cancer patients, and ICI treatment decisions in general, given the limited understanding of COVID-19 pathophysiology and the influence of ICI on the COVID-19 disease course.

In a second study, we thus performed scRNA-seq and scTCR-seq on BALF from COVID-19 and non-COVID-19 pneumonia patients (critical and mild disease). Our data suggested that a balanced immune response underlies mild COVID-19, in which T-cells and neutrophils effectuate the antiviral immune response coupled to phagocytic clearing by macrophages. In severe disease, viral clearing by T-cells was hampered (exemplified by reduced interferon signalling), leading to myeloid hyperinflammation. The body of evidence provided by our group and others yielded diagnostic and predictive biomarkers (e.g. BALF neutrophil-to-lymphocyte ratio), as well as a rationale for anti-inflammatory treatments (e.g. corticosteroids, anti-IL-6 and JAK inhibitors) for severe COVID-19. Longitudinal studies have shown that interferon signalling may be protective early while it may sustain myeloid inflammation late in the disease course. This likely explains clinical data showing that ICI therapy initiated prior to SARS-CoV-2 infection does not worsen COVID-19 outcomes.

In conclusion, by leveraging scRNA-seq, we have contributed to a better understanding of COVID-19 and ICI-pneumonitis pathophysiology, which is a valuable first step towards clinically useful diagnostics and therapeutics.

Date:1 Aug 2019 →  1 Aug 2023
Keywords:Non-small cell lung cancer, Single-Cell Analysis, Tumor Microenvironment, Biomarker research
Disciplines:Oncology not elsewhere classified
Project type:PhD project