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. 2023 Mar 20;30(3):3516-3528.
doi: 10.3390/curroncol30030267.

CXCL1 and CXCL6 Are Potential Predictors for HCC Response to TACE

Maximilian N Kinzler  1 , Katrin Bankov  2 , Julia Bein  2 , Claudia Döring  2 , Falko Schulze  2 , Henning Reis  2 , Scherwin Mahmoudi  3 , Vitali Koch  3 , Leon D Grünewald  3 , Angelika Stehle  1 , Dirk Walter  1 , Fabian Finkelmeier  1 , Stefan Zeuzem  1 , Peter J Wild  2   4   5 , Thomas J Vogl  3 , Simon Bernatz  2   3   4   6
Affiliations

CXCL1 and CXCL6 Are Potential Predictors for HCC Response to TACE

Maximilian N Kinzler et al. Curr Oncol. .

Abstract

Distinct immune patterns of hepatocellular carcinoma (HCC) may have prognostic implications in the response to transarterial chemoembolization (TACE). Thus, we aimed to exploratively analyze tumor tissue of HCC patients who do or do not respond to TACE, and to identify novel prognostic biomarkers predictive of response to TACE. We retrospectively included 15 HCC patients who had three consecutive TACE between January 2019 and November 2019. Eight patients had a response while seven patients had no response to TACE. All patients had measurable disease according to mRECIST. Corresponding tumor tissue samples were processed for differential expression profiling using NanoString nCounter® PanCancer immune profiling panel. Immune-related pathways were broadly upregulated in TACE responders. The top differentially regulated genes were the upregulated CXCL1 (log2fc 4.98, Benjamini-Hochberg (BH)-p < 0.001), CXCL6 (log2fc 4.43, BH-p = 0.016) and the downregulated MME (log2fc -4.33, BH-p 0.001). CD8/T-regs was highly increased in responders, whereas the relative number of T-regs to tumor-infiltrating lymphocytes (TIL) was highly decreased. We preliminary identified CXCL1 and CXCL6 as candidate genes that might have the potential to serve as therapeutically relevant biomarkers in HCC patients. This might pave the way to improve patient selection for TACE in HCC patients beyond expert consensus.

Keywords: biomarker; hepatocellular carcinoma; immune profiling; transarterial chemoembolization.

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Conflict of interest statement

H.R. was on an advisory board of Bristol-Myers Squibb; received honoraria from Roche, Bristol-Myers Squibb, Janssen-Cilag GmbH, Novartis, and Astra Zeneca; received travel support from Philips, Roche, and Bristol-Myers Squibb; received grants from Bristol-Myers Squibb; and holds shares of Bayer. F. F. has received travel support from Ipsen, and speaker fees from AbbVie, MSD, Ipsen, Eisai, and Fresenius. S.Z. has received speaker fees and/or honoraria for consultancy from AbbVie, Allergan, BioMarin, Gilead, Intercept, Janssen, MSD/Merck, NovoNordisk, SoBi, and Theratechnologies. P.J.W. has received consulting fees and honoraria for lectures by Bayer, Janssen-Cilag, Novartis, Roche, MSD, Astellas Pharma, Bristol-Myers Squibb, Thermo Fisher Scientific, Molecular Health, Guardant Health, Sophia Genetics, Qiagen, Eli Lilly, Myriad, Hedera Dx, and Astra Zeneca; research support was provided by Astra Zeneca. All other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
STARD flowchart of patient inclusion into the study. Abbreviations: standards for reporting diagnostic accuracy studies (STARD).
Figure 2
Figure 2
NanoString analysis reveals broad upregulation in immune pathway scores in TACE responders. (a) Unsupervised t-SNE plots of all normalized mRNA and (b) trend plot of pathway signatures. Abbreviations: messenger ribonucleic acid (mRNA), transarterial chemoembolization (TACE), T-distributed stochastic neighbor embedding (t-SNE).
Figure 3
Figure 3
Differentially expressed genes between responders and non-responders to TACE. (a) Volcano plot of all differentially expressed genes or (b) only strong and significantly deregulated genes (log2fc ≤ −2 or ≥2 and p-value < 0.05 with Benjamini–Hochberg correction). Volcano plot displaying each gene’s -log10(p-value) and log2 fold-change with the selected covariate. Statistically significant genes fall at the top of the plot above the horizontal line, and highly differentially expressed genes fall to either side. The horizontal line indicates BH-p < 0.05. Abbreviations: transarterial chemoembolization (TACE).
Figure 4
Figure 4
Cell type profiling reveals increased immune infiltrates in responders. (a) Absolute and (b) relative cell type scores are shown in responders (true) and non-responders (false). The nCounter® advanced analysis module of the PanCancer immune profiling panel uses genes whose expression is largely specific to certain immune cell populations to measure the abundance of these cell types. The module assumes that each cell type’s characteristic genes are expressed exclusively and consistently within the cell type. Under this model, a cell type’s abundance can be measured as the average log-scale expression of its characteristic genes. The cell type abundance measurements are plotted against response. True = responder, false = non-responder.
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