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. 2023 Dec 8;15(24):5759.
doi: 10.3390/cancers15245759.

Prognostic Implications of LRP1B and Its Relationship with the Tumor-Infiltrating Immune Cells in Gastric Cancer

Rui Wang  1   2 , Guangtao Zhang  1 , Xiaohong Zhu  1 , Yan Xu  1 , Nida Cao  1 , Zhaoyan Li  3 , Chen Han  1 , Mengmeng Qin  1 , Yumiao Shen  1 , Jiahuan Dong  1 , Fangqi Ma  1 , Aiguang Zhao  1
Affiliations

Prognostic Implications of LRP1B and Its Relationship with the Tumor-Infiltrating Immune Cells in Gastric Cancer

Rui Wang et al. Cancers (Basel). .

Abstract

Background: Recent studies have shown that low-density lipoprotein receptor-related protein 1b (LRP1B), as a potential tumor suppressor, is implicated in the response to immunotherapy. The frequency of LRP1B mutation gene is high in many cancers, but its role in gastric cancer (GC) has not been determined.

Methods: The prognostic value of LRP1B mutation in a cohort containing 100 patients having received radical gastrectomy for stage II-III GC was explored. By analyzing the data of LRP1B mRNA, the risk score of differentially expressed genes (DEGs) between LRP1B mutation-type and wild-type was constructed based on the TCGA-STAD cohort. The infiltration of tumor immune cells was evaluated by the CYBERSORT algorithm and verified by immunohistochemistry.

Results: LRP1B gene mutation was an independent risk factor for disease-free survival (DFS) in GC patients (HR = 2.57, 95% CI: 1.28-5.14, p = 0.008). The Kaplan-Meier curve demonstrated a shorter survival time in high-risk patients stratified according to risk score (p < 0.0001). CYBERSORT analysis showed that the DEGs were mainly concentrated in CD4+ T cells and macrophages. TIMER analysis suggested that LRP1B expression was associated with the infiltration of CD4+ T cells and macrophages. Immunohistochemistry demonstrated that LRP1B was expressed in the tumor cells (TCs) and immune cells in 16/89 and 26/89 of the cohort, respectively. LRP1B-positive TCs were associated with higher levels of CD4+ T cells, CD8+ T cells, and CD86/CD163 (p < 0.05). Multivariate analysis showed that LRP1B-positive TCs represented an independent protective factor of DFS in GC patients (HR = 0.43, 95% CI: 0.10-0.93, p = 0.042).

Conclusions: LRP1B has a high prognostic value in GC. LRP1B may stimulate tumor immune cell infiltration to provide GC patients with survival benefits.

Keywords: LRP1B; gastric cancer; immunochemistry; prognosis; tumor-infiltrating immune cells.

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Conflict of interest statement

The authors have no conflict of interest.

Figures

Figure 1
Figure 1
Constructing a nomogram integrating LRP1B and clinical factors. (A) The Lasso coefficient profiles of survival-related variables. (B) Tenfold cross-validation for turning parameter (lambda) selection in the LASSO model based on the minimum criteria for DFS. (C–E) ROC curve analysis at 1, 2, and 3 years of patients (AUC = 0.804, 0.809, 0.078). (F) Nomogram to predict disease-free survival probability at 1, 2, and 3 years. (G–I) Calibration curve for the nomogram predicting 1-, 2-, and 3-year disease-free survival.
Figure 2
Figure 2
Schematic diagram of LRP1B and differential expression analysis of TCGA-STAD based on LRP1B status. (A) The LRP1B genome information map. (B) mRNA expression in TCGA-STAD patients with LRP1BWT and LRP1BMUT. (C) Heatmap plot of mRNA expression in TCGA-STAD patients with LRP1BWT and LRP1BMUT. (D) Volcano plot of differentially expressed genes identified in TCGA-STAD patients with LRP1BWT and LRP1BMUT (DEGs: differentially expressed genes; WT: wild-type; MUT: mutation-type; The blue and green dots in Figure 2A represented different sites).
Figure 3
Figure 3
Development of the prognostic signature based on 15 DEGs identified in TCGA-STAD patients with LRP1BWT and LRP1BMUT. (A) The Lasso coefficient profiles of OS-related DEGs; (B) selection of 15 DEGs in the LASSO model based on the minimum criteria for prognosis. (C) Risk score distribution, survival status, and 15 DEG expression profiles for patients in high-risk and low-risk groups. (D) Difference in OS between high-risk and low-risk groups of the TCGA-STAD patients. (E) Time-dependent ROC curve analysis at 1, 2, and 3 years (DEGs: differentially expressed genes; WT: wild-type; MUT: mutation-type; OS: overall survival).
Figure 4
Figure 4
Immune infiltration landscape in LRP1B molecule. (A) Relative proportion of immune cell infiltrations in LRP1BWT and LRP1BMUT patients with TCGA-STAD. (B) Infiltration abundance of LRP1BWT and LRP1BMUT in 6 immune cells. (C) The relationship between the expression level of LRP1B and 6 kinds of immune infiltrating cells (WT: wild-type; MUT: mutation-type; ** p < 0.01).
Figure 5
Figure 5
Representative immunohistochemical staining of LRP1B and tumor-infiltrating immune cells in human gastric cancer tissue. (A) LRP1B expression on TCs (magnifications ×100; magnifications ×200). (B) LRP1B expression on ICs (magnifications ×100; magnifications ×200). (C) CD4+ TII expression on TCs (magnifications ×100; magnifications ×200). (D) CD8+ TII expression on TCs (magnifications ×100; magnifications ×200). (E) CD86+ TII expression on TCs (magnifications ×100; magnifications ×200). (F) CD163+ TII expression on TCs (magnifications ×100; magnifications ×200). (G) CD25+ TII expression on TCs (magnifications ×100; magnifications ×200) (TCs: tumor cells; ICs: immune cells; TIIs: tumor-infiltrating immune cells).
Figure 6
Figure 6
The relationship between LRP1B expression on TCs/ICs and TIIs in human gastric cancer tissue. (A) LRP1B expression on TCs with CD4+ TIIs. (B) LRP1B expression on TCs with CD8+ TIIs. (C) LRP1B expression on TCs with CD86+TIIs. (D) LRP1B expression on TCs with CD163+TIIs. (E) LRP1B expression on TCs with CD25+TIIs. (F) LRP1B expression on ICs with CD4+ TIIs. (G) LRP1B expression on ICs with CD8+ TIIs. (H) LRP1B expression on ICs with CD86+ TIIs. (I) LRP1B expression on ICs with CD163+ TIIs. (J) LRP1B expression on ICs with CD25+ TIIs (TCs: tumor cells; ICs: immune cells; TIIs: tumor-infiltrating immune cells).
Figure 7
Figure 7
Kaplan–Meier survival analysis of LRP1B expression on TCs/ICs in human gastric cancer tissue. (A) DFS of LRP1B expression on TCs. (B) OS of LRP1B expression on TCs. (C) DFS of LRP1B expression on ICs. (D) OS of LRP1B expression on ICs (TCs: tumor cells; ICs: immune cells; DFS: disease-free survival; OS: overall survival).
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