Oncotarget published "Molecular characterization of Kita-Kyushu lung cancer antigen (KK-LC-1) expressing carcinomas" which reported that cancer/testis antigens are strongly expressed in some solid tumors but minimally expressed in normal tissue, making them appealing therapeutic targets.
These authors characterized the molecular subtypes of non-small cell lung cancer expressing KK-LC-1 to inform rational clinical trials of T-cell receptor therapy targeting KK-LC-1. 9790 NSCLC tumors that underwent whole transcriptome sequencing and NextGen DNA sequencing at Caris Life Sciences were analyzed.
Tumors were split into quartiles based on KK-LC-1 expression and pathological and molecular differences were investigated. Tumors with the highest quartile of KK-LC-1 expression had a greater proportion of tumors with high tumor mutation burden. Higher levels of KK-LC-1 expression were seen in pan-wild type and KRAS mutated tumors and associated with high TMB.
Dr. Jorge J. Nieva from The University of Southern California said, "Cancer testis antigens (CTA) are germ cell antigens that are typically minimally expressed in normal tissues, but commonly expressed in tumors."
CTA has been shown to be expressed in 82% of gastric cancer tumors and 52.9% of breast cancer tumors, with even higher detection rates in triple negative breast cancer.
CTA has been shown to be expressed in 82% of gastric cancer tumors and 52.9% of breast cancer tumors, with even higher detection rates in triple negative breast cancer.
In lung cancer, surgical series have shown KK-LC-1 to be expressed in about one-third of lung cancer tumors.
T-cell receptor therapy is designed to modify patient T cells with a selected T-cell receptor targeting a cancer testis antigen which can promote selective targeting of tumor antigens while limiting off target toxicity.
Because the treatment algorithms have diverged between lung cancer subtypes that are amenable to targeted therapy or immunotherapy, positioning emerging treatments for future clinical trials requires understanding of which molecular subtype of lung cancer would be most appropriate for the new CTA directed immune treatments.
Figure 5: Tumor microenvironment in KK-LC-1 high vs low expressing (Q4 vs. Q1) in adenocarcinomas as measured by immune cell fraction calculated by QuantiSeq. The elements of the tumor microenvironment calculated include B cell, M1 macrophage, M2 macrophage, monocytes, myeloid dendritic cells, neutrophils, NK cells, CD4+ T cells, CD8+ T cells, and regulatory T cells.
Therefore, the aim of this study is to identify the molecular subtypes of lung cancer expressing KK-LC-1 to determine which patients would be most likely to benefit from a clinical trial of T cell receptor therapy targeting KK-LC-1.
The Nieva Research Team concluded in their Oncotarget Research Output, "There are several limitations of our study. First is that the study was performed using de-identified patient samples without the benefit of clinical history. Second, we did not include protein expression measurements which would be important for identification of lung cancer patients most likely to benefit from TCR-T therapy. Finally, although we identified those tumors with higher and lower numbers of transcripts for KK-LC-1, we do not know the threshold of gene expression that would be relevant for targeted T-cells or for any other targeted immunotherapy. Establishing this minimal level will require interventional studies with clinical endpoints. Future directions include investigation of other cancer testis antigens particularly those antigens that are candidates for T-cell based immunotherapy [6, 12]."
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DOI - https://doi.org/10.18632/oncotarget.28132
Correspondence to - Jorge J. Nieva - [email protected]
Keywords - lung cancer, tumor microenvironment, diagnostic biomarkers, biomarkers for immunotherapy, cancer testis antigen
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