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Published on: August 11, 2017
CCL20 Released by Drug-Tolerant Persisters Impairs Immunotherapy in EGFR-Mutant Lung Adenocarcinoma
Hoi-Hin Kwok1, Jiashuang Yang1, Nerissa Chui-Mei Lee1
1Department of Medicine Li Ka Shing Faculty of Medicine University of Hong Kong Hong Kong SAR China.
Abstract:
EGFR-mutant lung adenocarcinoma (LUAD) is typically associated with an immunosuppressive tumor immune microenvironment (TIME) and poor responses to PD-1 blockade. However, the contribution of drug-tolerant persister cells (DTPs) to immunotherapy resistance remains unclear. We hypothesized that DTPs-derived chemokine (C-C motif) ligand 20 (CCL20) promotes immune evasion and impairs PD-1-based immunotherapy in EGFR-mutant. To test this, humanized NSG mice engrafted with EGFR-mutant H1975 cells and human peripheral blood mononuclear cells (n = 6 per group) were administered with anti-PD-1 (200 µg) and/or anti-CCL20 (20 µg) every other day for a total of four doses. The combination reduced mean tumor volume by 65% compared with control treatment (p < 0.01). Single-cell RNA sequencing showed that cotreatment selectively suppressed CCL20 expression in DTP clusters and activated interferon-α and -γ signaling (ISG15, CMPK2). Multiplex immunofluorescence revealed combination treatment increased infiltration of M1-like macrophages, plasmacytoid dendritic cells, and memory B cells, alongside spatial segregation of CD4+ regulatory T cells (p < 0.05). These findings identify DTPs-derived CCL20 as a mediator of immunosuppressive TIME and support combined CCL20/PD-1 blockade as a potential therapeutic strategy for EGFR-mutant lung adenocarcinoma.
Insights
Drug-tolerant persister cells in EGFR-mutant lung adenocarcinoma produce CCL20, hindering immunotherapy. Blocking CCL20 with PD-1 inhibitors enhances anti-tumor immunity and reduces tumor growth.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- EGFR-mutant lung adenocarcinoma (LUAD) often presents an immunosuppressive tumor immune microenvironment (TIME).
- Resistance to PD-1 blockade immunotherapy is common in EGFR-mutant LUAD, with the role of drug-tolerant persister cells (DTPs) unclear.
Purpose of the Study:
- To investigate the role of DTPs-derived chemokine (C-C motif) ligand 20 (CCL20) in immune evasion and PD-1 blockade resistance in EGFR-mutant LUAD.
- To evaluate the efficacy of combined anti-CCL20 and anti-PD-1 therapy in a preclinical model.
Main Methods:
- Humanized NSG mice engrafted with EGFR-mutant H1975 cells and human peripheral blood mononuclear cells were treated with anti-PD-1 and/or anti-CCL20.
- Tumor volume, gene expression (single-cell RNA sequencing), and immune cell infiltration (multiplex immunofluorescence) were analyzed.
Main Results:
- Combined anti-CCL20 and anti-PD-1 treatment reduced mean tumor volume by 65% compared to control.
- Cotreatment suppressed CCL20 expression in DTPs, activated interferon signaling, and increased M1-like macrophages, plasmacytoid dendritic cells, and memory B cells.
- Combination therapy led to spatial segregation of CD4+ regulatory T cells.
Conclusions:
- DTPs-derived CCL20 mediates an immunosuppressive TIME in EGFR-mutant LUAD.
- Combined CCL20 and PD-1 blockade represents a promising therapeutic strategy for EGFR-mutant lung adenocarcinoma.
