Molecular characterization of Kita-Kyushu lung cancer antigen (KK-LC-1) expressing carcinomas.

Abstract

e21000 Background: Cancer/testis antigens (CTAs) are strongly expressed in some solid tumors but minimally expressed in normal tissue, making them appealing therapeutic targets. KK-LC-1 (CXorf61) has cytoplasmic expression in some types of gastric and breast cancer and reports of expression in one-third of lung cancer tumors. Here, we characterize the molecular subtype of lung cancers expressing KK-LC-1 to plan rational clinical trials of T-cell receptor therapy (TCR-T) targeting KK-LC-1. Methods: A total of 9790 non-small cell lung cancer (NSCLC) tumors that underwent whole transcriptome sequencing (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ) were analyzed. Tumors were split into quartiles based on KK-LC-1 expression and pathological and molecular differences were investigated. PD-L1 expression was tested by IHC using 22c3 (Dako) and TPS scores were reported. Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). Statistical significance was determined using chi-square/Fisher-Exact and adjusted for multiple comparisons (adjusted p < 0.05). Results: Adenocarcinoma had significantly higher KK-LC-1 expression than squamous cell carcinoma (median 3.25 vs. 1.17 transcripts per million (TPM), p < 0.0001). There is statistically higher expression of KK-LC-1 in pan wild type (3.95 TPM) compared to tumors with EGFR mutation (1.95 TPM), ALK fusion (0.6 TPM), MET exon-14-skip mutation (1.22 TPM), RET fusion (1.42 TPM), and ROS1 fusion (1.78 TPM). Tumors within the highest quartile of KK-LC-1 expression (Q4) had a greater proportion of TMB > 10 mutations per megabase (mt/MB) (44% vs. 28%) compared to Q1. No difference was seen in PD-L1 expression. In adenocarcinoma, Q4 had a higher TMB compared to Q1 (9 mt/MB vs. 5 mt/MB). There was a higher KRAS mutation prevalence in Q3/Q4 (34.8%/35.0%) than Q1/Q2 (22%/29%) but a lower ALK fusion prevalence in Q3/Q4 (1.0%/0.5%) compared to Q1/Q2 (3.3%/2.6%). Increased KK-LC-1 expression is associated with increased M1 Macrophage abundance. Conclusions: In our population, KK-LC-1 expression was higher in adenocarcinoma. Higher levels of KK-LC-1 expression were seen in pan-wild type and KRAS mutated tumors and associated with higher TMB while lower levels of expression were seen in driver positive cancers including EGFR, ALK, MET, RET and ROS1. TCR-T therapy directed against KK-LC-1 should be explored in patients whose clinical features reflect these characteristics.