PD-1/PD-L1 immune-checkpoint blockade induces immune effector cell modulation in metastatic non-small cell lung cancer patients: A single-cell flow cytometry approach
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Published on: February 5, 2020
Antonella Fameli1, Valerio Nardone2, Mojtaba Shekarkar Azgomi3
1Medical Oncology Unit, "Bianchi Melacrino Morelli" Grand Metropolitan Hospital, Reggio Calabria, Italy.
Insights
Immune-checkpoint blockade in metastatic non-small cell lung cancer (mNSCLC) alters peripheral immune cells. This may correlate with increased autoantibodies and immune-related adverse events, necessitating further research.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Peripheral immune-checkpoint blockade using monoclonal antibodies (mAbs) targeting programmed cell death receptor-1 (PD-1) or PD-Ligand-1 (PD-L1) is an emerging treatment for metastatic non-small cell lung cancer (mNSCLC).
- These mAbs aim to restore anti-tumor cytotoxic T lymphocyte (CTL) activity by disrupting the inhibitory PD-1/PD-L1 pathway, a natural mechanism preventing autoimmunity.
- Understanding the peripheral immune modulation induced by these therapies is crucial for managing potential side effects.
Purpose of the Study:
- To investigate the impact of PD-1/PD-L1 blockade on peripheral immune cell subsets in mNSCLC patients.
- To identify potential correlations between changes in immune cell populations and the development of autoantibodies and immune-related adverse events (irAEs).
Main Methods:
- Retrospective bioinformatics analysis using single-cell flow cytometry.
- Evaluation of peripheral blood immune cell subsets in 28 mNSCLC patients undergoing PD-1/PD-L1 blockade therapy.
- Assessment of autoantibody levels (e.g., antinuclear antibodies, extractable nuclear antigen antibodies) and irAEs.
Main Results:
- Treatment with PD-1/PD-L1 blocking mAbs was associated with a decrease in CD4+ T-cell and B-cell subsets and the neutrophil-to-lymphocyte ratio.
- An increase was observed in natural killer T (NKT) cells, CD8+PD1+ T cells, and eosinophils.
- Increased autoantibodies and irAEs were linked to the deregulation of specific immune subpopulations, notably NKT cells.
Conclusions:
- PD-1/PD-L1 immune-checkpoint blockade significantly alters peripheral immune cell composition in mNSCLC patients.
- Specific immune cell subset deregulation, particularly involving NKT cells, may be associated with treatment-related autoimmunity.
- Further correlative biological and clinical studies with deep immune monitoring are essential to fully characterize the effects of these therapies.
Abstract:
Peripheral immune-checkpoint blockade with mAbs to programmed cell death receptor-1 (PD-1) (either nivolumab or pembrolizumab) or PD-Ligand-1 (PD-L1) (atezolizumab, durvalumab, or avelumab) alone or in combination with doublet chemotherapy represents an expanding treatment strategy for metastatic non-small cell lung cancer (mNSCLC) patients. This strategy lays on the capability of these mAbs to rescue tumor-specific cytotoxic T lymphocytes (CTLs) inactivated throughout PD-1 binding to PD-L1/2 in the tumor sites. This inhibitory interactive pathway is a physiological mechanism of prevention against dangerous overreactions and autoimmunity in case of prolonged and/or repeated CTL response to the same antigen peptides. Therefore, we have carried out a retrospective bioinformatics analysis by single-cell flow cytometry to evaluate if PD-1/PD-L1-blocking mAbs modulate the expression of specific peripheral immune cell subsets, potentially correlated with autoimmunity triggering in 28 mNSCLC patients. We recorded a treatment-related decline in CD4+ T-cell and B-cell subsets and in the neutrophil-to-lymphocyte ratio coupled with an increase in natural killer T (NKT), CD8+PD1+ T cells, and eosinophils. Treatment-related increase in autoantibodies [mainly antinuclear antibodies (ANAs) and extractable nuclear antigen (ENA) antibodies] as well as the frequency of immune-related adverse events were associated with the deregulation of specific immune subpopulations (e.g., NKT cells). Correlative biological/clinical studies with deep immune monitoring are badly needed for a better characterization of the effects produced by PD-1/PD-L1 immune-checkpoint blockade.
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