Page 16 - SDIR5 Abstract book 21 12 2021.

ADVANCES IN SOLID TUMOR RESEARCH

Mesenchymal properties and immune checkpoint pathways in small cell lung cancer (SCLC)
stem cells

1
Gunes Esendagli
1 Hacettepe University Cancer Institute, Ankara, Turkey

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. Even though the immune regulatory capacities of CSCs are well-acknowledged, their
influence on the anti-tumor immunity in SCLC remains to be better elucidated. 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.

3