SIR 2024
Interventional Oncology
Santosh Mandal, PhD
researcher
MD Anderson Cancer Center
Financial relationships: Full list of relationships is listed on the CME information page.
Poonam Yadav, PhD
Post Doctoral Fellow
University of Texas MD Anderson Cancer Center
Disclosure information not submitted.
Malea Williams, n/a
Research Investigator
Department of Interventional Radiology at The University of Texas MD Anderson Cancer Center
Disclosure information not submitted.
Rahul A. Sheth, MD
Associate Professor
University of Texas MD Anderson Cancer Center
Financial relationships: Full list of relationships is listed on the CME information page.
There is a growing appreciation for the influence of the peripheral nervous system on cancer progression (1,2). Modulation of sympathetic signaling to the liver may represent a new therapeutic approach for hepatocellular carcinoma (HCC). The purpose of this study was to investigate in a preclinical model the effects of sympathetic neurolysis combined with systemic checkpoint inhibition in HCC tumors.
Materials and Methods:
An HCC model was established using orthotopic subcapsular implantation of 1 x 10^7 HCA-1 hepatoma cells into the livers of C3H mice through mini-laparotomy. After achieving the target tumor volume, mice were randomized into neurolysis and sham groups. A neurotoxin, 6-hydroxydopamine (6-OHDA), was administered intraperitoneally at a dose of 200 mg/kg for five consecutive days to ablate peripheral sympathetic nerve terminals. Mice were further randomized to receive either anti-PD1 antibody or vehicle control. The PD-1 inhibitor was administered intraperitoneally at 250 µg per injection on days 0, 3, and 6. On day 7, the animals were euthanized, and samples of blood, liver, and spleen tissues were collected for analysis. Liver tumor sections were processed for conventional H&E staining and spatial phenotyping using Lunaphore/Opal staining. Flow cytometry was employed to analyze various immune cell types in the liver tumor and blood samples.
Results:
Intraperitoneal injection of 6-OHDA successfully ablated sympathetic nerve fibers in both the liver and liver tumors. This was confirmed via anti-tyrosine hydroxylase, NF-H, and CD31 staining. Neurolysis altered the tumor immune microenvironment by reducing inhibitory signals generated by myeloid-derived suppressor cells. This was further corroborated by increased infiltration of activated effector CD8+ T cells into the primary tumor. The treatment also led to an increased ratio of CD8+T cells to Treg cells and decreased colocalization of CD8+ T cells with immunosuppressive cells in the tumor microenvironment.
Conclusion:
Neurolysis effectively modulates the local tumor immune microenvironment, thereby enhancing the efficacy of immune checkpoint inhibition in HCC tumors.