The profound and long-lasting response to immune checkpoint inhibitors (ICIs) in a subset of non-small cell lung cancer (NSCLC) patients makes it urgent the need of predictive biomarkers. As critical modulators of the tumor microenvironment, STK11 and Galectin-3 (Gal-3) demonstrated significant impact on patient outcome. Thus, we aimed to dissect the prognostic and predictive role of STK11 and Gal-3 tissue expression in ICI-treated advanced NSCLC.
Tissue and peripheral blood (PB) samples were collected at baseline from 25 consecutive NSCLC undergoing ICI. STK11 and Gal-3 expression was detected by Immunohistochemistry (IHC). STK11 mutation was determined by Next Generation Sequencing (NGS) in a subset of cases (n: 8, so far - other cases are ongoing). Soluble PD-L1 (sPD-L1) (immunoassay), PB CD8+PD1+ and NK cells (FACS) together with inflammatory features including LDH were measured. Tissue parameters were correlated with clinical outcome and circulating immune profile.
Absence of STK11 expression by IHC (STK11neg) was detected in 18 (72%) NSCLC among which 74% were KRAS-mutant. Lack of STK11 expression at tissue and genomic levels was concordant in 62%. STK11neg cases displayed a trend towards a worse PFS (median PFS [mPFS], 4.3 vs 13.5 months, P = 0.09) and OS (median OS, 12.8 months vs not reached, P = 0.190). Although PFS was shorter in Gal-3high (2+/3+ IHC) cases, Gal-3 status did not impact on OS nor DCR. Significantly higher sPD-L1 levels (P = 0.037) and lower circulating NK (P = 0.042) were observed in STK11neg cases, while Gal-3high were associated to higher LDH values and lower CD3+ and NK. Patients carrying STK11neg/Gal-3high tumors had significantly reduced PFS (mPFS, 1.7 vs 13.5 months, P = 0.001) and lower benefit from ICI (DCR, 30% vs 80%, P = 0.03) compared to their counterpart. Moreover, STK11neg/Gal-3high signature had a relevant impact on CD4+, CD8+ and NK number and LDH levels.
STK11neg and Gal-3high may represent a poor prognostic trait in ICI-treated NSCLC patients. The correlation of STK11 and Galectin with circulating factors underlies a close interplay between tissue and peripheral blood compartments, ultimately featuring the tumor-host interaction and the proneness to respond to ICIs.
Legal entity responsible for the study
University Hospital of Parma.
Has not received any funding.
All authors have declared no conflicts of interest.