Cancer-testis antigen KK-LC-1 is a potential biomarker associated with immune cell infiltration in lung adenocarcinoma

Abstract

Background: Cancer-testis antigens (CTAs) have emerged as potential clinical biomarkers targeting immunotherapy. KK-LC-1 is a member of CTAs, which has been demonstrated in a variety of tumors tissues and been found to elicit immune responses in cancer patients. However, the expression level and immune infiltration role of KK-LC-1 in lung adenocarcinoma (LUAD) remains to be elucidated.

Methods: In this study, the mRNA expression and overall survival rate of KK-LC-1 were evaluated by the TIMER and TCGA database in LUAD tissues and KK-LC-1 expression was further validated by clinical serum samples using quantitative RT-PCR. The relationship of KK-LC-1 with clinicopathologic parameters was analyzed. ROC curve result showed that miR-1825 was able to distinguish preoperative breast cancer patients from healthy people and postoperative patients. Then, the ROC curves were used to examine the ability of KK-LC-1 to distinguish preoperative LUAD patients from healthy and postoperative patients. The correlation between KK-LC-1 and infiltrating immune cells and immune marker sets was investigated via TIMER, TISIDB database, and CIBERSORT algorithm. The Kaplan-Meier plotter was used to further evaluate the prognostic value based on the expression levels of KK-LC-1 in related immune cells.

Results: The results showed that KK-LC-1 was significantly over-expressed in LUAD, and high levels of expression of KK-LC-1 were also closely correlated with poor overall survival. We also found that KK-LC-1 associated with TMN stage, NSE and CEA. The ROC curve result showed that KK-LC-1 was able to distinguish preoperative LUAD cancer patients from healthy people and postoperative patients. Moreover, KK-LC-1 had a larger AUC with higher diagnostic sensitivity and specificity than CEA. Based on the TIMER, TISIDB database, and CIBERSORT algorithm, the expression of KK-LC-1 was negatively correlated with CD4+ T cell, Macrophage, and Dendritic Cell in LUAD. Moreover, Based on the TIMER database, KK-LC-1 expression had a remarkable correlation with the type markers of Monocyte, TAM, M1 Macrophage, and M2 Macrophage. Furthermore, KK-LC-1 expression influenced the prognosis of LUAD patients by directly affecting immune cell infiltration by the Kaplan-Meier plotter analysis.

Conclusions: In conclusion, KK-LC-1 may serve as a promising diagnostic and prognostic biomarker in LUAD and correlate with immune infiltration and prognosis.

Keywords: Cancer-testis antigen; KK-LC-1; Lung adenocarcinoma; Prognosis; Tumor immune infiltration.

Fig. 1

KK-LC-1 expression in various human cancers and related to prognosis in LUAD. A Human KK-LC-1 expression in various tumors according to the TIMER database. B The expression levels of KK-LC-1 in LUAD and para-cancerous lung tissues. C KK-LC-1 expression in LUAD and matched normal tissues by TCGA database. D The overall survival rate of KK-LC-1 expression in LUAD

Fig. 2

KK-LC-1 expression in serum and related to diagnosis in LUAD. A The expression level of KK-LC-1in LUAD serum and healthy person’s serum. ROC curve of serum B KK-LC-1 and C CEA. D KK-LC-1 expression in LUAD patient’s preoperative and postoperative serum. E ROC curve of serum KK-LC-1 to validate pre-operative cases from post-operative in LUAD

Fig. 3

Association of KK-LC-1 expression with immune infiltration in LUAD according to the TIMER database. A The correlation between KKLC and immune cells by TIMER. B The correlation between KKLC and immune cells by TISIDB. C 22 types of tumor-infiltrating immune cells were analyzed in high and low KK-LC-1 expression groups

Fig. 4

Association of KK-LC-1 expression with immune marker sets in LUAD based on TIMER database. The correlation between KK-LC-1 expression and the gene markers of A Monocyte (CD68 and CSF1R); B TAM (CD68, IL10 and CCL2); C M1 Macrophage (NOS2, IRF5 and PTGS2); D M2 Macrophage (CD163,VSIG4 and MS4A4A)

Fig. 5

The prognostic value of high and low expression of KK-LC-1 in LUAD according to immune cell subgroups using Kaplan-Meier potter. The increased and decreased expression of KK-LC-1 in various immune cell subgroups have diverse prognosis in LUAD (A-H)