Dhanasekaran Lab

Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease

Hepatocellular carcinoma (HCC) frequently recurs from minimal residual disease (MRD), which persists after therapy. Here, we identified mechanisms of persistence of residual tumor cells using post-chemoembolization human HCC (n = 108 patients, 1.07 million cells) and a transgenic mouse model of MRD. Through single-cell high-plex cytometric imaging, we identified a spatial neighborhood within which PD-L1 + M2-like macrophages interact with stem-like tumor cells, correlating with CD8+ T cell exhaustion and poor survival. Further, through spatial transcriptomics of residual HCC, we showed that macrophage-derived TGFβ1 mediates the persistence of stem-like tumor cells. Last, we demonstrate that combined blockade of Pdl1 and Tgfβ excluded immunosuppressive macrophages, recruited activated CD8+ T cells and eliminated residual stem-like tumor cells in two mouse models: a transgenic model of MRD and a syngeneic orthotopic model of doxorubicin-resistant HCC. Thus, our spatial analyses reveal that PD-L1+ macrophages sustain MRD by activating the TGFβ pathway in stem-like cancer cells and targeting this interaction may prevent HCC recurrence from MRD.

 

MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma That Is Reversible through Restoration of Proinflammatory Macrophages

Cancers evade immune surveillance, which can be reversed through immune-checkpoint therapy in a small subset of cases. Here, we report that the MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. In 33 different human cancers, MYC genomic amplification and overexpression increased immune-checkpoint expression, predicted nonresponsiveness to immune-checkpoint blockade, and was associated with both Th2-like immune profile and reduced CD8 T-cell infiltration. MYC transcriptionally suppressed innate immunity and MHCI-mediated antigen presentation, which in turn impeded T-cell response. The immune evasion induced by MYC in HCC can be overcome by combined PDL1 and CTLA4 blockade.

https://doi.org/10.1158/0008-5472.CAN-22-0232

Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers

Vascular invasion (VI) is a critical risk factor for HCC recurrence and poor survival. The molecular drivers of vascular invasion in HCC are open for investigation. Deciphering the molecular landscape of invasive HCC will help identify therapeutic targets and noninvasive biomarkers. 

Our study evaluates the molecular landscape of tumors with VI, identifying distinct transcriptional, epigenetic, and proteomic changes driven by the MYC oncogene. We show that MYC up-regulates fibronectin expression, which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising noninvasive proteomic biomarker of VI in HCC.

https://doi.org/10.1002/hep.31614

Spontaneous Regression of Hepatocellular Carcinoma: When the Immune System Stands Up to Cancer

Spontaneous regression of cancer is rare and has been observed mostly in immunogenic cancers like melanoma. A few cases of spontaneous regression of hepatocellular carcinoma (HCC) have been reported, but the mechanisms of regression have not been elucidated. Here, we report a patient with advanced HCC who experienced spontaneous regression of her tumor and present evidence for a putative immune-mediated mechanism for tumor regression.

https://doi.org/10.1002/hep.31489

MYC and Twist1 cooperate to drive metastasis by eliciting crosstalk between cancer and innate immunity

Metastasis is a major cause of cancer mortality. We generated an autochthonous transgenic mouse model whereby conditional expression of MYC and Twist1 enables hepatocellular carcinoma (HCC) to metastasize in >90% of mice. MYC and Twist1 cooperate and their sustained expression is required to elicit a transcriptional program associated with the activation of innate immunity, through secretion of a cytokinome that elicits recruitment and polarization of tumor associated macrophages (TAMs). Systemic treatment with Ccl2 and Il13 induced MYC-HCCs to metastasize; whereas, blockade of Ccl2 and Il13 abrogated MYC/Twist1-HCC metastasis. Further, in 33 human cancers (n = 9502) MYC and TWIST1 predict poor survival (p=4.3×10−10), CCL2/IL13 expression (p<10−109) and TAM infiltration (p<10−96). Finally, in the plasma of patients with HCC (n = 25) but not cirrhosis (n = 10), CCL2 and IL13 were increased and IL13 predicted invasive tumors. Therefore, MYC and TWIST1 generally appear to cooperate in human cancer to elicit a cytokinome that enables metastasis through crosstalk between cancer and immune microenvironment.

DOI: 10.7554/eLife.50731

MYC ASO Impedes Tumorigenesis and Elicits Oncogene Addiction in Autochthonous Transgenic Mouse Models of HCC and RCC

 

The MYC oncogene is dysregulated in most human cancers and hence is an attractive target for cancer therapy. We and others have shown experimentally in conditional transgenic mouse models that suppression of the MYC oncogene is sufficient to induce rapid and sustained tumor regression, a phenomenon known as oncogene addiction. However, it is unclear whether a therapy that targets the MYC oncogene could similarly elicit oncogene addiction. In this study, we report that using antisense oligonucleotides (ASOs) to target and reduce the expression of MYC impedes tumor progression and phenotypically elicits oncogene addiction in transgenic mouse models of MYC-driven primary hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC).

 

DOI:https://doi.org/10.1016/j.omtn.2020.07.008

Other Recent Articles

  • Adeniji N, Arjunan V, Prabhakar V, Mannalithara A, Ghaziani T, Ahmed A, Kwo P, Nguyen M, Melcher ML, Busuttil RW, Florman SS, Haydel B, Ruiz RM, Klintmalm GB, Lee DD, Burcin Taner C, Hoteit MA, Verna EC, Halazun KJ, Tevar AD, Humar A, Chapman WC, Vachharajani N, Aucejo F, Nydam TL, Markmann JF, Mobley C, Ghobrial M, Langnas AN, Carney CA, Berumen J, Schnickel GT, Sudan DL, Hong JC, Rana A, Jones CM, Fishbein TM, Agopian V, Dhanasekaran R. Posttransplant Outcomes in Older Patients With Hepatocellular Carcinoma Are Driven by Non-Hepatocellular Carcinoma Factors. Liver Transpl [Internet]. 2020 Dec 11; Available from: http://dx.doi.org/10.1002/lt.25974
  • Adeniji N, Arjunan V, Prabhakar V, Tulu Z, Kambham N, Ahmed A, Kwo P, Dhanasekaran R. Impact of Bridging Locoregional Therapies for Hepatocellular Carcinoma on Post‐Transplant Clinical Outcome. (2020). Clinical Transplantation. https://doi.org/10.1111/ctr.14128
  • Swaminathan S, Hansen A, Heftdal LD, Dhanasekaran R*, Deutzmann A, Liefwalker DF, Horton C, Mosley A, Liebersbach M, Maecker H, Felsher DW. MYC Functions as a Switch for Natural Killer Cell-Mediated Immune Surveillance of Lymphoid Malignancies. Nat Commun. 2020 Jun.  DOI: 10.1038/s41467-020-16447-7
  • Lai I, Swaminathan S, Baylot V, Mosley A, Dhanasekaran R*, Gabay M, Felsher DW. Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma. J Immunother Cancer. 2018 Nov 20;6(1):125. https://jitc.biomedcentral.com/articles/10.1186/s40425-018-0431-x
  • Dhanasekaran R, Gabay-Ryan, M, Baylot V, Lai I, Mosley A, Huang X, Zabludoff S, Li J, Kaimal V, Karmali P, Felsher D. Anti-miR-17 Therapy Delays Tumorigenesis in MYC-driven Hepatocellular Carcinoma (HCC). Oncotarget. 2018 Jan 19;9(5):5517-5528. https://www.oncotarget.com/article/22342/text/


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