Small cell lung cancer stem cells display mesenchymal properties and exploit immune checkpoint pathways in activated cytotoxic T lymphocytes

Small cell lung cancer (SCLC) is an aggressive tumor type with early dissemination and distant metastasis capacity. Even though optimal chemotherapy responses are observed initially in many patients, therapy resistance is almost inevitable. Accordingly, SCLC has been regarded as an archetype for can...

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Published in:Cancer Immunology, Immunotherapy Immunotherapy, 2022-02, Vol.71 (2), p.445-459
Main Authors: Kursunel, M. Alper, Taskiran, Ekim Z., Tavukcuoglu, Ece, Yanik, Hamdullah, Demirag, Funda, Karaosmanoglu, Beren, Ozbay, Feyza Gul, Uner, Aysegul, Esendagli, Dorina, Kizilgoz, Derya, Yilmaz, Ulku, Esendagli, Gunes
Format: Article
Language:English
Subjects:
Apoptosis
B7-H1 Antigen - metabolism
Cancer Research
CD44 antigen
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
CD90 antigen
Cell culture
Cell differentiation
Cell Proliferation
Chemotherapy
CTLA-4 protein
Cytotoxicity
Humans
Hyaluronan Receptors - metabolism
Immune checkpoint
Immunology
Immunomodulation
Immunotherapy
Lung cancer
Lung Neoplasms - immunology
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Lymph nodes
Lymphocytes
Lymphocytes T
Medicine
Medicine & Public Health
Mesenchymal Stem Cells - immunology
Mesenchymal Stem Cells - metabolism
Mesenchymal Stem Cells - pathology
Mesenchyme
Metastases
Neoplastic Stem Cells - immunology
Neoplastic Stem Cells - metabolism
Neoplastic Stem Cells - pathology
Oncology
Original
Original Article
PD-1 protein
PD-L1 protein
Programmed Cell Death 1 Ligand 2 Protein - metabolism
Small cell lung carcinoma
Small Cell Lung Carcinoma - immunology
Small Cell Lung Carcinoma - metabolism
Small Cell Lung Carcinoma - pathology
Stem cells
T-Lymphocytes, Cytotoxic - immunology
Tumor Cells, Cultured
Tumors
γ-Interferon
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Summary:Small cell lung cancer (SCLC) is an aggressive tumor type with early dissemination and distant metastasis capacity. Even though optimal chemotherapy responses are observed initially in many patients, therapy resistance is almost inevitable. Accordingly, SCLC has been regarded as an archetype for cancer stem cell (CSC) dynamics. To determine the immune-modulatory influence of CSC in SCLC, this study focused on the characterization of CD44 + CD90 + CSC-like subpopulations in SCLC. These cells displayed mesenchymal properties, differentiated into different lineages and further contributed to CD8 + cytotoxic T lymphocytes (CTL) responses. The interaction between CD44 + CD90 + CSC-like cells and T cells led to the upregulation of checkpoint molecules PD-1, CTLA-4, TIM-3, and LAG3. In the patient-derived lymph nodes, CD44 + SCLC metastases were also observed with T cells expressing PD-1, TIM-3, or LAG3. Proliferation and IFN-γ expression capacity of TIM-3 and LAG3 co-expressing CTLs are adversely affected over long-time co-culture with CD44 + CD90 + CSC-like cells. Moreover, especially through IFN-γ secreted by the T cells, the CSC-like SCLC cells highly expressed PD-L1 and PD-L2. Upon a second encounter with immune-experienced, IFN-γ-stimulated CSC-like SCLC cells, both cytotoxic and proliferation capacities of T cells were hampered. In conclusion, our data provide evidence for the superior potential of the SCLC cells with stem-like and mesenchymal properties to gain immune regulatory capacities and cope with cytotoxic T cell responses. With their high metastatic and immune-modulatory assets, the CSC subpopulation in SCLC may serve as a preferential target for checkpoint blockade immunotherapy .
ISSN:0340-7004
1432-0851
DOI:10.1007/s00262-021-02998-1