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Hepatology International
Published in: Hepatology International 2/2024

Open Access 04-05-2023 | Metastasis | Original Article

Hepatocellular carcinoma (HCC) tumor microenvironment is more suppressive than colorectal cancer liver metastasis (CRLM) tumor microenvironment

Authors: Sara Santagata, Giuseppina Rea, Daniela Castaldo, Maria Napolitano, Anna Capiluongo, Crescenzo D’Alterio, Anna Maria Trotta, Caterina Ieranò, Luigi Portella, Salvatore Di Maro, Fabiana Tatangelo, Vittorio Albino, Rita Guarino, Carmen Cutolo, Francesco Izzo, Stefania Scala

Published in: Hepatology International | Issue 2/2024

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Abstract

Background and purpose

While HCC is an inflammation-associated cancer, CRLM develops on permissive healthy liver microenvironment. To evaluate the immune aspects of these two different environments, peripheral blood-(PB), peritumoral-(PT) and tumoral tissues-(TT) from HCC and CRLM patients were evaluated.

Methods

40 HCC and 34 CRLM were enrolled and freshly TT, PT and PB were collected at the surgery. PB-, PT- and TT-derived CD4+CD25+ Tregs, M/PMN-MDSC and PB-derived CD4+CD25− T-effector cells (Teffs) were isolated and characterized. Tregs’ function was also evaluated in the presence of the CXCR4 inhibitor, peptide-R29, AMD3100 or anti-PD1. RNA was extracted from PB/PT/TT tissues and tested for FOXP3, CXCL12, CXCR4, CCL5, IL-15, CXCL5, Arg-1, N-cad, Vim, CXCL8, TGFβ and VEGF-A expression.

Results

In HCC/CRLM-PB, higher number of functional Tregs, CD4+CD25hiFOXP3+ was detected, although PB-HCC Tregs exert a more suppressive function as compared to CRLM Tregs. In HCC/CRLM-TT, Tregs were highly represented with activated/ENTPD-1+Tregs prevalent in HCC. As compared to CRLM, HCC overexpressed CXCR4 and N-cadherin/vimentin in a contest rich in arginase and CCL5. Monocytic MDSCs were highly represented in HCC/CRLM, while high polymorphonuclear MDSCs were detected only in HCC. Interestingly, the function of CXCR4-PB-Tregs was impaired in HCC/CRLM by the CXCR4 inhibitor R29.

Conclusion

In HCC and CRLM, peripheral blood, peritumoral and tumoral tissues Tregs are highly represented and functional. Nevertheless, HCC displays a more immunosuppressive TME due to Tregs, MDSCs, intrinsic tumor features (CXCR4, CCL5, arginase) and the contest in which it develops. As CXCR4 is overexpressed in HCC/CRLM tumor/TME cells, CXCR4 inhibitors may be considered for double hit therapy in liver cancer patients.
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Metadata
Title
Hepatocellular carcinoma (HCC) tumor microenvironment is more suppressive than colorectal cancer liver metastasis (CRLM) tumor microenvironment
Authors
Sara Santagata
Giuseppina Rea
Daniela Castaldo
Maria Napolitano
Anna Capiluongo
Crescenzo D’Alterio
Anna Maria Trotta
Caterina Ieranò
Luigi Portella
Salvatore Di Maro
Fabiana Tatangelo
Vittorio Albino
Rita Guarino
Carmen Cutolo
Francesco Izzo
Stefania Scala
Publication date
04-05-2023
Publisher
Springer India
Published in
Hepatology International / Issue 2/2024
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-023-10537-6

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WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

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