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

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 gastric, breast, and lung cancer. We characterized the molecular subtypes of non-small cell lung cancer (NSCLC) expressing KK-LC-1 to inform rational clinical trials of T-cell receptor therapy (TCR-T) targeting KK-LC-1. 9790 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. 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). Tumors with the highest quartile of KK-LC-1 expression had a greater proportion of tumors with high tumor mutation burden (TMB) (≥10 mutations per megabase; 44% vs. 28% in Q1, p < 0.001). Increased KK-LC-1 expression was associated with increased M1 macrophage abundance. Higher levels of KK-LC-1 expression were seen in pan-wild type and KRAS mutated tumors and associated with high TMB. TCR-T therapy directed against KK-LC-1 should be considered in patients whose clinical features reflect these characteristics.
Competing Interests: CONFLICTS OF INTEREST Dr. Nieva receives personal fees from Astra Zeneca, Fujirebio and Naveris. He receives research support from Merck and Genentech. Dr. Hsu was a consultant for Targeted Healthcare Communications. Ms. Baca and Dr. Xiu are employees of Caris Life Sciences. Dr. Kim is a consultant or advisory board member for Novartis, Janssen, AstraZeneca, and PierianDx and has received research funding to his institution from AstraZeneca, Bristol-Myers Squibb, Novartis, Genentech, Regeneron, Spectrum, Mirati, Debiopharm, Karyopharm, and Janssen. Dr. Mamdani is a consultant for Zentalis and has been a consultant for AstraZeneca, Caris Life Sciences, and Takeda. Dr. Nagasaka is a consultant for Caris and a speaker for Blueprint. She has also participated in advisory boards for AstraZeneca, Daiichi, Takeda, Novartis, EMD Serono, JNJ, Pfizer, Lilly, Genentech, and has received travel support from AnHeart Therapuetics. Dr. Puri is a consultant/advisor for AstraZeneca and G1 Therapeutics. Dr. Liu is a consultant/serves on advisory board for Amgen, AstraZeneca, Bayer, Beigene, Blueprint, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/MSD, Novartis, Regeneron, Takeda, Turning Point Therapeutics. He also has received research funding to his institution from Alkermes, Bayer, Blueprint, Bristol-Myers Squibb, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics. Dr. Korn is an employee of Caris Life Sciences and has stock ownership and stock options from Caris Life Sciences. He also receives consultant fees from Merck. All other authors have no conflicts of interests to disclose.
(Copyright: © 2021 Hsu et al.)