Phenotypic Characteristics of the Tumour Microenvironment in Primary and Secondary Hepatocellular Carcinoma
(1) Background: The intra-tumoural heterogeneity (ITH) of hepatocellular carcinoma (HCC) and its microenvironment (TME) across primary and secondary disease is poorly characterised. (2) Methods: Intra-tumoural (IT) and peri-tumoural (PT) staining of matched primary and secondary samples was conducted to evaluate the distribution of CD4+/FOXP3+ and CD8+/PD1+ T-cells. Samples underwent PD-L1/2 immunostaining, tumour mutational burden (TMB) evaluation, and high-resolution T-cell receptor (TCR) sequencing to derive T-cell clonality and targeted transcriptomics. (3) Results: We analysed 24 samples from matched primary (n = 11) and secondary (n = 13; 5 synchronous, 6 metachronous) deposits, 11 being extrahepatic (84.6%). IT CD8+ density was lower than PT in both primary (p = 0.005) and secondary deposits (p = 0.01), consistent with immune exclusion. PD-L1+ tumours displayed higher IT and PT CD8+/PD1+ cell density compared to PD-L1- (p < 0.05), and primary IT infiltrate was enriched in CD4+/FOXP3+ cells, compared to PT regions (p = 0.004). TCR-sequencing demonstrated enrichment of the top T-cell clonotype in secondary versus primary HCC (p = 0.02), without differences in overall productive clonality (p = 0.35). TMB was similar across primary versus secondary HCC (p = 0.95). While directed gene set analysis demonstrated the uniformity of transcriptional signatures of individual immune cell types, secondary deposits demonstrated higher COLEC12 (p = 0.004), CCL26 (p = 0.02), CD1E (p = 0.02) and CD36 (p = 0.03) expression with downregulation of CXCL1 (p = 0.03), suggesting differential regulation of innate immunity. (4) Conclusion: Immune exclusion is a defining feature of the HCC TME. Despite evidence of homogeneity in somatic TMB, secondary HCC is characterised by the expansion of a distinct T-cell clonotype and differential regulation of innate immune pathways.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
Cancers - 13(2021), 9 vom: 29. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fessas, Petros [VerfasserIn] |
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| Links: |
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| Themen: |
Hepatocellular carcinoma |
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| Anmerkungen: |
Date Revised 20.09.2023 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.3390/cancers13092137 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM324996373 |
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| 520 | |a (1) Background: The intra-tumoural heterogeneity (ITH) of hepatocellular carcinoma (HCC) and its microenvironment (TME) across primary and secondary disease is poorly characterised. (2) Methods: Intra-tumoural (IT) and peri-tumoural (PT) staining of matched primary and secondary samples was conducted to evaluate the distribution of CD4+/FOXP3+ and CD8+/PD1+ T-cells. Samples underwent PD-L1/2 immunostaining, tumour mutational burden (TMB) evaluation, and high-resolution T-cell receptor (TCR) sequencing to derive T-cell clonality and targeted transcriptomics. (3) Results: We analysed 24 samples from matched primary (n = 11) and secondary (n = 13; 5 synchronous, 6 metachronous) deposits, 11 being extrahepatic (84.6%). IT CD8+ density was lower than PT in both primary (p = 0.005) and secondary deposits (p = 0.01), consistent with immune exclusion. PD-L1+ tumours displayed higher IT and PT CD8+/PD1+ cell density compared to PD-L1- (p < 0.05), and primary IT infiltrate was enriched in CD4+/FOXP3+ cells, compared to PT regions (p = 0.004). TCR-sequencing demonstrated enrichment of the top T-cell clonotype in secondary versus primary HCC (p = 0.02), without differences in overall productive clonality (p = 0.35). TMB was similar across primary versus secondary HCC (p = 0.95). While directed gene set analysis demonstrated the uniformity of transcriptional signatures of individual immune cell types, secondary deposits demonstrated higher COLEC12 (p = 0.004), CCL26 (p = 0.02), CD1E (p = 0.02) and CD36 (p = 0.03) expression with downregulation of CXCL1 (p = 0.03), suggesting differential regulation of innate immunity. (4) Conclusion: Immune exclusion is a defining feature of the HCC TME. Despite evidence of homogeneity in somatic TMB, secondary HCC is characterised by the expansion of a distinct T-cell clonotype and differential regulation of innate immune pathways | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a hepatocellular carcinoma | |
| 650 | 4 | |a intra-tumoural heterogeneity | |
| 650 | 4 | |a tumour microenvironment | |
| 700 | 1 | |a Spina, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Boldorini, Renzo L |e verfasserin |4 aut | |
| 700 | 1 | |a Pirisi, Mario |e verfasserin |4 aut | |
| 700 | 1 | |a Minisini, Rosalba |e verfasserin |4 aut | |
| 700 | 1 | |a Mauri, Francesco A |e verfasserin |4 aut | |
| 700 | 1 | |a Simpson, Fraser |e verfasserin |4 aut | |
| 700 | 1 | |a Olivieri, Paola |e verfasserin |4 aut | |
| 700 | 1 | |a Gennari, Alessandra |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Ching Ngar |e verfasserin |4 aut | |
| 700 | 1 | |a Siddique, Abdul |e verfasserin |4 aut | |
| 700 | 1 | |a Goldin, Robert D |e verfasserin |4 aut | |
| 700 | 1 | |a Akarca, Ayse U |e verfasserin |4 aut | |
| 700 | 1 | |a Marafioti, Teresa |e verfasserin |4 aut | |
| 700 | 1 | |a Pinato, David J |e verfasserin |4 aut | |
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