SCLC is an aggressive malignancy where immunotherapies show limited efficacy. We aimed
to characterize the SCLC microenvironment according to the expression patterns of
SCLC subtype markers and novel immune checkpoints to identify therapeutic vulnerabilities.We
included SCLC tissue samples from 219 surgically resected, limited-stage patients
in this cross-sectional study. We performed immunohistochemistry for STING and MHCII,
as well as for the novel subtype markers (ASCL1, NEUROD1, POU2F3, YAP1). Moreover,
we assessed CD45 + , CD8 + and CD68 + immune cell infiltration.36% of SCLC tumors
showed significant stromal or intraepithelial CD45 + immune cell infiltration. These
patients exhibited significantly increased overall survival (OS) (vs. patients with
immune-deserted tumors). High CD8 expression was associated with increased median
OS. We found STING expression on cancer-associated fibroblasts in the stroma and on
T-cells and macrophages in both tumorous and stromal compartments. STING expression
positively correlated with immune cell infiltration. Increased STING-positivity in
tumor nests was an independent favorable prognosticator for OS. ASCL1 was the most
frequently expressed subtype-specific protein. Concomitant expression of three or
four subtype-defining markers was seen in 13.8% of the included samples, whereas 24.1%
of the cases were classified as quadruple negative tumors. YAP1 expression was associated
with increased immune infiltrates. Tumor cell MHCII expression positively correlated
with immune cell infiltration and with STING- and YAP1 expressions.STING and MHCII
are expressed in SCLC. The majority of immune-infiltrated SCLCs exhibit increased
STING expression. Immune infiltration and STING expression are prognostic in limited-stage
SCLC, making STING a potential therapeutic target.
