KK-LC-1: A Potential Biomarker for Predicting Immunotherapy Response in Liver Cancer

Liver cancer is the second leading cause of cancer-related death worldwide. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4, has shown promise in reducing tumor size and prolonging survival. However, its effectiveness remains limited, with only about 20% of patients responding positively. The high cost, frequent immune-related adverse events, and occasional cases of hyper-progressive disease make it crucial to identify reliable biomarkers that can predict treatment response.

Existing biomarkers, such as PD-L1 expression, microsatellite instability (MSI), and tumor mutation burden (TMB), are not always effective in liver cancer. The low PD-L1 expression in liver tumors and the rare occurrence of MSI and high TMB mean that alternative predictive markers are needed. This study investigates the potential of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a cancer-testis antigen, as a new biomarker for predicting the efficacy of immunotherapy in liver cancer patients.

KK-LC-1 Expression in Liver Cancer

Researchers analyzed liver cancer tissue samples and corresponding serum samples from patients undergoing immunotherapy. Immunohistochemistry (IHC) was used to measure KK-LC-1 expression in tumor tissues, while antibody levels in the blood were examined for potential correlation with treatment outcomes.

In a study involving 131 liver cancer patients, KK-LC-1 was highly expressed in 34.4% of cases. However, when looking at data from a larger cohort of 340 hepatocellular carcinoma (HCC) patients in The Cancer Genome Atlas (TCGA) database, higher KK-LC-1 expression was associated with significantly shorter overall survival.

Among 24 patients who received immunotherapy, KK-LC-1 expression was significantly linked to overall survival. Patients with higher KK-LC-1 levels tended to have prolonged survival, suggesting that this antigen could play a role in predicting who will benefit from immunotherapy. Additionally, the study found that KK-LC-1 expression was correlated with Foxp3, a regulatory immune cell marker, further supporting its potential role in shaping the tumor immune environment.

Changes in KK-LC-1 Antibody Levels During Immunotherapy

To further explore its role as a biomarker, the study examined KK-LC-1 antibody levels in 20 patients receiving immunotherapy. The results showed that patients whose disease remained stable after treatment had significantly higher KK-LC-1 antibody levels than those who experienced a partial response. Interestingly, among patients who did show a positive response, KK-LC-1 antibody levels tended to decline over time, suggesting a dynamic relationship between treatment response and antigen presence in the bloodstream.

The Role of KK-LC-1 in the Immune System and Tumor Progression

Further laboratory experiments revealed that KK-LC-1 might influence immune response through the MAPK signaling pathway. Gene expression analysis identified 118 differentially expressed genes between tumor cells with high and low KK-LC-1 expression, including TGFA and PDGFB, both of which are involved in tumor growth and immune evasion.

The study also demonstrated that KK-LC-1 antigenic peptides could stimulate T cells to produce gamma interferon, a key immune signaling molecule. Reactive T cells were found to specifically kill tumor cells with high KK-LC-1 expression, suggesting that KK-LC-1 could serve as a potential immunotherapy target.

The findings suggest that KK-LC-1 could be an important biomarker for predicting immunotherapy response in liver cancer. Patients with high KK-LC-1 expression may be more likely to benefit from immune checkpoint inhibitors. Measuring KK-LC-1 antibody levels in the blood could provide a non-invasive method for monitoring treatment response and making real-time adjustments to therapy.

KK-LC-1’s role as a cancer-testis antigen also makes it a promising target for vaccine-based immunotherapy. Given its restricted expression in normal tissues, developing a KK-LC-1-targeted vaccine could stimulate the immune system to attack tumors while minimizing damage to healthy cells. The study’s findings pave the way for further research into KK-LC-1-based treatments, including mRNA vaccines and T-cell therapies.

To learn more, read this!: KK-LC-1, a biomarker for prognosis of immunotherapy for primary liver cancer | BMC Cancer | Full Text