Leow, W. Q. | Search bioRxiv

bioRxiv2024

Single-cell and spatial atlas of steatotic liver-related hepatocellular carcinoma

Steatotic liver disease-related hepatocellular carcinoma (SLD-HCC) poses significant challenges in liver cancer management. Our current study investigates the tumor microenvironment (TME) of SLD-HCC using single-cell transcriptomic, proteomic and spatial transcriptomic analyses. We identified altered immune-related and lipid metabolism pathways, particularly in regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs) within the SLD-HCC microenvironment, suggesting distinct cellular adaptations to a high-fat TME and general immunosuppression. Cytometry by time-of-flight revealed a cold and immunosuppressive TME depleted with CD8+ T cells and enriched with Tregs, while spatial transcriptomics uncovered a unique spatial architecture with Treg/CAF clusters specifically located at the tumor margins in SLD-HCC. Crucially, we identified Treg-CAF interactions as a key mediator associated with lack of response to immunotherapy in SLD-HCC. Our findings highlight the intricate immune dynamics of SLD-HCC, indicating potential therapeutic targets to counteract immune evasion and restore anti-tumor immunity in SLD-HCC. HighlightsO_LIThe TME of SLD-HCC exhibits altered immune and lipid pathways C_LIO_LIImmunosuppressive SLD-HCC TME is depleted with CD8+ T cells and enriched with Tregs C_LIO_LISLD-HCC has a unique spatial architecture with Treg-CAF clusters at tumor margins C_LIO_LITreg-CAF interaction via TNFSF14-TNFRSF14 axis mediates immunotherapy resistance C_LI

immunology↗

bioRxiv2019

CD38 is a good predictor of anti-PD-1 immunotherapy responsiveness in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality in the world. However, with the associated low five-year survival and high recurrence rates, alternative treatment modalities specifically immunotherapy have been researched. A correlation between CD38+ tumour-infiltrating leukocyte (TIL) density and improved prognosis was found in a recent study. However, studies relating to CD38 expression in immune infiltrates within tumours are limited. In the present study, we confirmed the expression of CD38 on macrophages in HCC and determined the relationship between CD38+ leukocytes and lymphocytes and patient response to immunotherapy. Using immunohistochemistry, we analysed tissue samples obtained from 20 patients from Singapore with HCC prior to immunotherapy. Tumour infiltrating leukocytes expression within tumour were correlated to the responsiveness of patients to immunotherapy.\n\nExpression of CD38 was found within the tumour cells and surrounding immune infiltrates including lymphocytes and macrophages. We then ask whether CD38 expression by the distinct cell populations may acquire theranostic relevance. Patients with higher level of CD38+ immune infiltrate subsets had significantly better response to anti-PD-1 immunotherapy, and this is also true for CD38+ lymphocytes within the tumour microenvironment. In particular, a cut-off of 13.0% positive out of total leukocytes and 12.4% positive out of total lymphocytes is found to be of strong predictive value of responsiveness to immunotherapy treatment, thus a strong theranostic impact is seen by using CD38 as a biomarker for anti-PD-1 therapy.\n\nThe establishment of an association between CD38 expression and the response to anti-PD-1 immunotherapy in HCC, could be applied to a larger cohort outside Singapore. These may eventually change the routine testing in clinical practice to identify HCC patients suitable for immunotherapy.

cancer biology↗