Multi-Scale Spatial Analysis of the Tumor Microenvironment Reveals Features of Cabozantinib and Nivolumab Efficacy in Hepatocellular Carcinoma.

Abstract

Background:

Concomitant inhibition of vascular endothelial growth factor (VEGF) and programmed cell death protein 1 (PD-1) or its ligand PD-L1 is a standard of care for patients with advanced hepatocellular carcinoma (HCC), but only a minority of patients respond, and responses are usually transient. Understanding the effects of therapies on the tumor microenvironment (TME) can provide insights into mechanisms of therapeutic resistance.

Methods:

14 patients with HCC were treated with the combination of cabozantinib and nivolumab through the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. Among them, 12 patients (5 responders + 7 non-responders) underwent successful margin negative resection and are subjects to tissue microarray (TMA) construction containing 37 representative tumor region cores. Using the TMAs, we performed imaging mass cytometry (IMC) with a panel of 27-cell lineage and functional markers. All multiplexed images were then segmented to generate a single-cell dataset that enables (1) tumor-immune compartment analysis and (2) cell community analysis based on graph-embedding methodology. Results from these hierarchies are merged into response-associated biological process patterns.

Results:

Image processing on 37 multiplexed-images discriminated 59,453 cells and was then clustered into 17 cell types. Compartment analysis showed that at immune-tumor boundaries from NR, PD-L1 level on tumor cells is significantly higher than remote regions; however, Granzyme B expression shows the opposite pattern. We also identify that the close proximity of CD8+ T cells to arginase 1hi (Arg1hi) macrophages, rather than CD4+ T cells, is a salient feature of the TME in non-responders. Furthermore, cell community analysis extracted 8 types of cell-cell interaction networks termed cellular communities (CCs). We observed that in non-responders, macrophage-enriched CC (MCC) and lymphocyte-enriched CC (LCC) strongly communicate with tumor CC, whereas in responders, such communications were undermined by the engagement between MCC and LCC.

Conclusion:

These results demonstrate the feasibility of a novel application of multiplexed image analysis that is broadly applicable to quantitative analysis of pathology specimens in immuno-oncology and provides further evidence that CD163-Arg1hi macrophages may be a therapeutic target in HCC. The results also provide critical information for the development of mechanistic quantitative systems pharmacology models aimed at predicting outcomes of clinical trials.

• Authors: Haoyang Mi, Won Jin Ho, Mark Yarchoan, Aleksander S Popel
• Journal: Frontiers in immunology (Front Immunol) Vol. 13 Pg. 892250 ( 2022) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 35634309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Mi, Ho, Yarchoan and Popel.

Chemical References

• Anilides
• B7-H1 Antigen
• Pyridines
• Vascular Endothelial Growth Factor A
• cabozantinib
• Nivolumab

Topics

• Anilides
• B7-H1 Antigen (metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Carcinoma, Hepatocellular (pathology)
• Humans
• Liver Neoplasms (pathology)
• Nivolumab (therapeutic use)
• Pyridines
• Spatial Analysis
• Tumor Microenvironment
• Vascular Endothelial Growth Factor A (metabolism)