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Co-Expression and Combined Prognostic Value of CSPG4 and PDL1 in TP53-Aberrant Triple-Negative Breast Cancer
Zhe-Yu Hu1,2,3, Chanjuan Zheng4,5, Jianbo Yang1,6,7
1Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, China.
Background:
In triple-negative breast cancer (TNBC), PDL1/PD1-directed immunotherapy is effective in less than 20% of patients. In our preliminary study, we have found CSPG4 to be highly expressed together with PDL1 in TNBCs, particularly those harboring TP53 aberrations. However, the clinical implications of co-expressed CSPG4 and PDL1 in TNBCs remain elusive.
Methods:
A total of 85 advanced TNBC patients treated in the Hunan Cancer Hospital between January 2017 and August 2019 were recruited. The expressions of CSPG4 and PDL1 in TNBC tissues were investigated using immunohistochemistry (IHC). The RNA-seq dataset from the TCGA-BRCA project was further used to analyze the mRNA expression of CSPG4 and PDL1 in TP53-aberrant TNBCs. Cox proportional hazards model and Kaplan-Meier curves with Logrank test was used to analyze the effects of CSPG4 and PDL1 on survival. TNBC cell lines were further used to investigate the molecular mechanism that were involved.
Results:
TP53 aberrations occurred in more than 50% of metastatic TNBCs and were related to higher tumor mutation burden (TMB). In TCGA-BRCA RNA-seq dataset analysis, both CSPG4 and PDL1 levels were high in TNBCs, especially in TP53-aberrant TNBCs. IHC assay showed nearly 60% of advanced TNBCs to be CSPG4-positive and about 25% to be both CSPG4-positive and PDL1-positive. The levels of CSPG4 and PDL1 were high in TNBC cell lines as revealed by flow cytometry and immunoblotting compared with non-TNBC cells. Univariate Cox regression analysis indicated that CSPG4 positivity was a significant risk factor for progression-free survival in metastatic TNBCs, with a hazard ratio (HR) of 2.26 (P = 0.05). KM curves with Logrank test also identified high level of CSPG4 as a significant risk factor for overall survival in advanced breast cancers in TCGA-BRCA samples (P = 0.02). The immunoblotting assays showed that EMT-related pathways were involved in CSPG4-mediated invasion.
Conclusions:
CSPG4 expression level is associated with PDL1 positivity in TP53-aberrant TNBC cells. Patients with CSPG4 expression have poor treatment response and poor overall survival. Co-expressed CSPG4 and PDL1 may have an important prognostic value and provide new therapeutic targets in TNBC patients. CSPG4 might mediate tumor invasion and PDL1 overexpression through EMT-related pathway.
Insights
Chondroitin sulfate proteoglycan 4 (CSPG4) and PDL1 are highly expressed in triple-negative breast cancer (TNBC), especially with TP53 aberrations. CSPG4 expression is linked to poor survival and may offer new therapeutic targets in TNBC.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Immunotherapy targeting PDL1/PD1 is effective in less than 20% of triple-negative breast cancer (TNBC) patients.
- Chondroitin sulfate proteoglycan 4 (CSPG4) is highly expressed with PDL1 in TNBC, particularly in tumors with TP53 aberrations.
- The clinical significance of co-expressed CSPG4 and PDL1 in TNBC is not well understood.
Purpose of the Study:
- To investigate the clinical implications of CSPG4 and PDL1 co-expression in advanced TNBC.
- To analyze the association between CSPG4, PDL1, TP53 status, and patient survival.
- To explore the potential molecular mechanisms involving CSPG4 in TNBC progression.
Main Methods:
- Retrospective analysis of 85 advanced TNBC patients.
- Immunohistochemistry (IHC) to assess CSPG4 and PDL1 expression in tumor tissues.
- TCGA-BRCA RNA-seq data analysis for CSPG4 and PDL1 mRNA levels, especially in TP53-aberrant TNBCs.
- Survival analysis using Cox proportional hazards models and Kaplan-Meier curves.
- In vitro studies using TNBC cell lines to investigate molecular mechanisms.
Main Results:
- TP53 aberrations were found in over 50% of metastatic TNBCs and correlated with higher tumor mutation burden.
- High CSPG4 and PDL1 mRNA levels were observed in TNBCs, particularly those with TP53 aberrations.
- IHC revealed CSPG4 positivity in nearly 60% and co-positivity for CSPG4 and PDL1 in about 25% of advanced TNBCs.
- CSPG4 positivity was a significant risk factor for progression-free survival (HR=2.26, P=0.05) and high CSPG4 levels predicted poor overall survival (P=0.02).
- EMT-related pathways were implicated in CSPG4-mediated invasion.
Conclusions:
- CSPG4 expression is associated with PDL1 positivity and poor prognosis in TP53-aberrant TNBC.
- Co-expressed CSPG4 and PDL1 hold prognostic value and represent potential therapeutic targets for TNBC.
- CSPG4 may drive tumor invasion and PDL1 overexpression via EMT-related pathways.
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