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. 2024 Jun 11;25(12):6423.
doi: 10.3390/ijms25126423.

Peripheral Blood CD8+ T-Lymphocyte Immune Response in Benign and Subpopulations of Breast Cancer Patients

Marek Lenárt  1 , Peter Bober  2 , Miroslav Marcin  2 , Soňa Tkáčiková  2 , Mária Kacírová  3 , Michal Alexovič  2 , Dávid Tóth  4 , Natália Madárová  1 , Jozef Radoňak  1 , Peter Urdzík  4 , Ján Fedačko  3 , Ján Sabo  2
Affiliations

Peripheral Blood CD8+ T-Lymphocyte Immune Response in Benign and Subpopulations of Breast Cancer Patients

Marek Lenárt et al. Int J Mol Sci. .

Abstract

Peripheral blood CD8+ T lymphocytes play a crucial role in cell-mediated immunity and tumor-related immune responses in breast cancer. In this study, label-free quantification analysis and gene set enrichment analysis (GSEA) of CD8+ T lymphocytes in the peripheral blood of benign patients and patients with different breast cancer (BC) subtypes, i.e., luminal A, luminal B, and triple-negative breast cancer (TNBC), were performed using nano-UHPLC and Orbitrap mass spectrometry. Differential protein expression in CD8+ T lymphocytes revealed significant downregulation (log2 FC ≥ 0.38 or ≤-0.38, adj. p < 0.05), particularly in proteins involved in cytotoxicity, cytolysis, and proteolysis, such as granzymes (GZMs) and perforin 1 (PRF1). This downregulation was observed in the benign group (GZMH, GZMM, and PRF1) and luminal B (GZMA, GZMH) subtypes, whereas granzyme K (GZMK) was upregulated in TNBC in comparison to healthy controls. The RNA degradation pathway was significantly downregulated (p < 0.05, normalized enrichment score (NES) from -1.47 to -1.80) across all BC subtypes, suggesting a potential mechanism for regulating gene expression during T cell activation. Also, the Sm-like proteins (LSM2, LSM3, and LSM5) were significantly downregulated in the RNA degradation pathway. Proteomic analysis of CD8+ T lymphocytes in peripheral blood across different breast cancer subtypes provides a comprehensive view of the molecular mechanisms of the systemic immune response that can significantly contribute to advancements in the diagnosis, treatment, and prognosis of this disease.

Keywords: CD8+ T lymphocytes; RNA degradation; breast cancer; granzymes.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Volcano plots of the differentially expressed proteins in CD8+ T lymphocytes between the (A) benign, (B) luminal A, (C) luminal B, and (D) TNBC vs. healthy control. An online web tool (SRPlot) was used to create volcano charts (https://www.bioinformatics.com, accessed on 13 May 2024) (adjusted p-value less than 0.05 and log2 FC ≥ 0.38 or ≤−0.38).
Figure 2
Figure 2
(A) Venn diagram showing overlapping and unique subtype-specific proteins. Blue: benign; red: luminal A; green: luminal B; Yellow: TNBC. PRF1, GZMA, GZMH, GZMK and GZMM proteins that were significantly altered (log2 FC ≥ 0.38 or ≤−0.38, adjusted p-value < 0.05) and participated in T cell-mediated cytotoxicity and cytolysis. LSM2, LSM3, and LSM5 proteins were significantly altered (log2 FC ≥ 0.38 or ≤−0.38, p-value < 0.05) and participated in the RNA catabolic (degradation) process. (B) Box plot of differentially expressed proteins PRF1, GZMH and GZMM that were downregulated in the benign group and GZMK that was upregulated in TNBC.
Figure 3
Figure 3
Bubble plots from the Kyoto Encyclopedia of Genes and Genomes (KEGG) of differentially expressed genes (DEGs) of the CD8 T lymphocytes obtained among the different groups, i.e., (A) benign, (B) luminal A, (C) luminal B and (D) TNBC vs. healthy controls. The color indicates the p-value (from the lowest in green to the highest in red), and the bubble size indicates the number of genes. The rich factor represents the proportion of the total number of genes.
Figure 4
Figure 4
GSEA analysis of quantified proteins in CD8+ T lymphocytes in benign (A), luminal A (B), luminal B (C) and TNBC (D). Enrichment plot: KEGG RNA degradation; benign (NES = −1.80, p < 0.01), luminal A (NES = −1.62, p = 0.02), luminal B (NES = −1.47, p = 0.05) and TNBC (NES = −1.75, p = 0.01).
Figure 5
Figure 5
A total of 59 proteins involved in RNA degradation (KEGG pathway: hsa03018). Pink colored boxes represent 44 differentially expressed proteins found in this pathway (https://www.genome.jp/pathway/map03018, accessed on 13 March 2024).
Figure 6
Figure 6
Gene ontology (GO) term enrichment analysis of genes (q-value threshold 0.05) using GOnet server (http://tools.dice-database.org/GOnet/, accessed on 14 May 2024). GO trees were built using biological process terms in a hierarchical layout. (A) T cell-mediated cytotoxicity, cytolysis and proteolysis (B) RNA catabolic process.
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