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Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence
Open accessPublished version of a preprint
Abstract
BACKGROUND: Novel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients. Little is known about the inter- and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie responses to modern systemic therapy. METHODS: We applied spatial transcriptomics (ST) profiling to characterize the tumor microenvironment in HCC resection specimens from a prospective clinical trial of neoadjuvant cabozantinib, a multi-tyrosine kinase inhibitor that primarily blocks VEGF, and nivolumab, a PD-1 inhibitor in which 5 out of 15 patients were found to have a pathologic response at the time of resection. RESULTS: ST profiling demonstrated that the TME of responding tumors was enriched for immune cells and cancer-associated fibroblasts (CAF) with pro-inflammatory signaling relative to the non-responders. The enriched cancer-immune interactions in responding tumors are characterized by activation of the PAX5 module, a known regulator of B cell maturation, which colocalized with spots with increased B cell marker expression suggesting strong activity of these cells. HCC-CAF interactions were also enriched in the responding tumors and were associated with extracellular matrix (ECM) remodeling as there was high activation of FOS and JUN in CAFs adjacent to the tumor. The ECM remodeling is consistent with proliferative fibrosis in association with immune-mediated tumor regression. Among the patients with major pathologic responses, a single patient experienced early HCC recurrence. ST analysis of this clinical outlier demonstrated marked tumor heterogeneity, with a distinctive immune-poor tumor region that resembles the non-responding TME across patients and was characterized by HCC-CAF interactions and expression of cancer stem cell markers, potentially mediating early tumor immune escape and recurrence in this patient. CONCLUSIONS: These data show that responses to modern systemic therapy in HCC are associated with distinctive molecular and cellular landscapes and provide new targets to enhance and prolong responses to systemic therapy in HCC.
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- Zhang S, Yuan L, Danilova L, Mo G, Zhu Q, Deshpande A, et al. Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular GEO Accession viewer. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE238264. Accessed 1 Aug 2023. · DOI
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Biomarkers for immunotherapy of hepatocellular carcinoma
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Metadata
- Authors
- Zhang, S., Yuan, L., Danilova, L., Mo, G., Zhu, Q., Deshpande, A., Bell, A. T. F., Elisseeff, J., Popel, A. S., Anders, R. A., Jaffee, E. M., Yarchoan, M., Fertig, E. J., & Kagohara, L. T.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Fertig, Elana J.
- Kagohara, Luciane T.
- ORCID
- Venue
- Genome Medicine
- Published
- 2023-09-18
- Volume
- 15
- Issue
- 1
- Pages
- 72-72
- ISSN
- 1756-994X (ISSN-L)
- PMC
- PMC10506285
- OpenAlex
- W4386834775
- Cited by
- 140
- References
- 33
- Citations by year
- 2026: 41 · 2025: 43 · 2024: 50 · 2023: 6
- FWCI
- 24.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome Medicine (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Maryland Cancer Moonshot Research Grant to the Johns Hopkins Medical Institutions
- Stand Up To Cancer
- NIH/NCI
- Allegheny Health Network
- Exelixis
- Bristol-Myers Squibb
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- hepatocellular carcinoma, cabozantinib, nivolumab, neoadjuvant therapy, tumor microenvironment, spatial transcriptomics, tyrosine kinase inhibitor resistance, anti-PD-1 resistance, cancer-associated fibroblasts, PAX5, B cell activation, extracellular matrix remodeling, tumor heterogeneity, cancer stem cells, immune evasion, tumor recurrence, immune cell infiltration
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