Chitinase 3-like-1 <i>(CHI3L1):</i> A potential prognostic biomarker for immunotherapy (IO) in non-small cell lung cancer (NSCLC).
Authors: Hina Khan, Nishant Gandhi, Suchitra Kamle, Bing Ma, Chun Geun Lee, Joanne Xiu, Ari Vanderwalde, Gilberto Lopes, Balasz Halmos, Christopher G. Azzoli, Jack A. Elias
Journal: Journal of Clinical Oncology (2025)

e20622 Background: CHI3L1 is a member of the 18-glycosyl hydrolase gene family and is produced by a variety of cells including tumors and immune cells. It is overexpressed in several cancers and involved in cell death, innate immunity and tissue repair. Recent preclinical studies report that CHI3L1 regulates anti-tumor immune responses by inducing PD-1, PD-L1/2 and CTLA-4. Here we present the largest real-world dataset, investigating the association of tumor CHI3L1 RNA expression and clinical outcomes with immune checkpoint inhibitors in NSCLC. Methods: A total of 26,100 NSCLC specimens with paired DNA and RNA underwent gene expression profiling at Caris Life Sciences (Phoenix, AZ). Samples were stratified into quartiles based on CHI3L1 expression: top (Q4) and bottom (Q1). Tumors with known oncogenic drivers (DP) and lacking driver alterations (DN) were studied. PD-L1 expression was analyzed by IHC (22c3). Survival was calculated from claims data using Kaplan-Meier estimates as follows: survival on IO (IO-OS) from initiation of IO to last contact; and Pembrolizumab time on treatment (Pembro-ToT) from initiation to termination of Pembrolizumab. Hazard ratios (HR) and p-values were calculated using Cox proportional hazards model and log-rank test. Multiple hypothesis corrections were made where applicable (q &lt; 0.05). Results: Compared to Q1, patients with Q4 tumors had a higher median age (70 vs 68), more females (54 vs 44%), non-smokers (5 vs 3%) and predominantly adenocarcinoma (AD) histology (67 vs 54%), all q &lt; 0.05. Among drivers, KRAS (31 vs 25%) BRAF (5 vs 3%) and ALK alterations (6 vs 1%) were more prevalent in Q4 (all q &lt; 0.05). Mutations in RB1 (6 vs 11%) , KEAP1 (9 vs 18%), STK11 (9 vs 16%) and TP53 (62 vs 71%, all q &lt; 0.05) were less prevalent in Q4. In keeping with our report that CHI3L1 stimulates immune checkpoints, PD-L1+ (TPS &gt; 50%: 37 vs 22% and 1-49%: 32 vs 26%, both q &lt; 0.05) was more prevalent in Q4 and immune checkpoint expression ( CTLA4 , CD274 , HAVCR2 , IDO1 : 2.5-3.2 fold higher) and immune cell infiltrates (B-cells, neutrophils, M1 and M2 macrophages: 1.2-2 fold higher) were enriched in Q4 (all q &lt; 0.05). Importantly, the enhanced expression of CHI3L1 in Q4 patients was associated with favorable IO-OS and Pembro-ToT; across AD and squamous histology and across DP and DN tumors (Table). Conclusions: CHI3L1 is a compelling biomarker in NSCLC that associates enhanced expression of immune checkpoints and tumor and microenvironment inflammation. Notably, high CHI3L1 is also associated with longer IO-OS and Pembro-ToT, likely due to the effects of CHI3L1 on tumor and microenvironment inflammation. Further studies correlating CHI3L1 expression are warranted, to establish its utility as a biomarker for OS and IO response. Survival in Q4 vs. Q1- only statistically significant associations displayed. HR IO-OS Pembro-ToT AD 0.7 0.8 SQ 0.8 0.8 KRAS+ 0.6 0.8 Driver- 0.8 0.8