MLXIPL associated with tumor-infiltrating CD8+ T cells is involved in poor prostate cancer prognosis

Abstract

Introduction: Within tumor microenvironment, the presence of preexisting antitumor CD8+ T Q7 cells have been shown to be associated with a favorable prognosis in most solid cancers. However, in the case of prostate cancer (PCa), they have been linked to a negative impact on prognosis.

Methods: To gain a deeper understanding of the contribution of infiltrating CD8+ T cells to poor prognosis in PCa, the infiltration levelsof CD8+ T cells were estimated using the TCGA PRAD (The Cancer Genome Atlas Prostate Adenocarcinoma dataset) and MSKCC (Memorial Sloan Kettering Cancer Center) cohorts.

Results: Bioinformatic analyses revealed that CD8+ T cells likely influence PCa prognosis through increased expression of immune checkpoint molecules and enhanced recruitment of regulatory T cells. The MLXIPL was identified as the gene expressed in response to CD8+ T cell infiltration and was found to be associated with PCa prognosis. The prognostic role of MLXIPL was examined in two cohorts: TCGA PRAD (p = 2.3E-02) and the MSKCC cohort (p = 1.6E-02). Subsequently, MLXIPL was confirmed to be associated with an unfavorable prognosis in PCa, as evidenced by an independent cohort study (hazard ratio [HR] = 2.57, 95% CI: 1.42- 4.65, p = 1.76E-03).

Discussion: In summary, the findings suggested that MLXIPL related to tumor-infiltrating CD8+ T cells facilitated a poor prognosis in PCa.

Keywords: CD8+ T cell; MLXIPL; cohort study; prognosis; prostate cancer.

Figure 1

CD8+ T cells infiltration associated with poor prognosis in PCa. (A) Biochemical recurrence-free survival for CD8+ T cells in TCGA dataset; (B) Biochemical recurrence-free survival for CD8+ T cells in MSKCC dataset.

Figure 2

The changes of TME in response to infiltrated CD8+ T cells. (A) Oncoplots across tumor-infiltrating CD8+ T cells and comparison of TMBs; (B) The mutation frequency analysis of SNPs in TCGA; (C) Immune checkpoint genes in low and high infiltrated CD8+ T cell groups; (D) The fraction of tumor-infiltrating immune cells across the density of CD8+ T cells. ns, not significant, *p< 0.05, **p< 0.01, ***p< 0.001, ****p< 0.0001.

Figure 3

Functional enrichment analysis of differentially expressed genes in response to CD8+ T cells. (A) Venn plots of differentially expressed genes identified by Wilcoxon rank sum and signed rank test, DESeq2 and edgeR; (B) Volcano plot of differential expression genes; (C) LASSO with biochemical recurrence as the endpoint; (D) Functional enrichment analysis based on KEGG database.

Figure 4

MLXIPL induced poor PCa prognosis in TCGA PRAD. (A) Survival analysis of biochemical recurrence for MLXIPL expression (top tertile vs bottom tertile) in TCGA PRAD; (B) ROC curves of biochemical recurrence in 1, 3 and 5 year(s); (C) Immune checkpoint genes out of LM22 matrix expressed in response to MLXIPL expression (top binary vs bottom binary); (D) The fraction of tumor-infiltrating immune cells across MLXIPL expression (top binary vs bottom binary). ns, not significant, *p< 0.05, **p< 0.01, ***p< 0.001.

Figure 5

Validation of the role MLXIPL in MSKCC cohort. (A) Biochemical recurrence-free survival for MLXIPL (top tertile vs bottom tertile); (B) ROC curves of biochemical recurrence in 1, 3 and 5 year(s); (C) Immune checkpoint relevant genes out of LM22 matrix expressed in low and high MLXIPL groups (top binary vs bottom binary); (D) The fraction of tumor-infiltrating immune cells across MLXIPL expression (top binary vs bottom binary). ns, not significant, *p< 0.05, **p< 0.01, ***p< 0.001, ****p< 0.0001.

Figure 6

Validation of the role MLXIPL in NanTong cohort. (A) Overall survival for MLXIPL (top tertile vs bottom tertile); (B) ROC curves of overall survival in 1-, 3- and 5-year(s); (C) Nomogram for overall survival of PCa. ROC, receiver operating characteristic.