Immune modulation by molecularly targeted photothermal ablation in a mouse model of advanced hepatocellular carcinoma and cirrhosis

Abstract

Immunotherapy is a promising new treatment approach for hepatocellular carcinoma (HCC), but there are numerous barriers to immunotherapy in HCC, including an immunosuppressive microenvironment and the “immunotolerance” of the liver. Hyperthermia treatment modalities are standard of care for early stage HCC, and hyperthermia is known to have immunomodulatory effects. We have developed a molecularly targeted photothermal ablation (MTPA) technology that provides thermally tunable, tumor-specific heat generation. The purpose of this study was to evaluate the morphologic and immunologic effects of MTPA in an immunotherapy-resistant syngeneic mouse model of HCC in a background of toxin-induced cirrhosis. We found that the anatomic, cellular, and molecular features of this model recapitulate the characteristics of advanced human HCC. MTPA as a monotherapy and in combination with immune checkpoint therapy significantly increased intratumoral CD3+ and activated CD8+ T cells while decreasing regulatory T cells relative to control or immune checkpoint therapy alone based on immunohistochemistry, flow cytometry, and single cell RNA sequencing data. Furthermore, we identified evidence of MTPA’s influence on systemic tumor immunity, with suppression of remote tumor growth following treatment of orthotopic tumors. The results of this study suggest that tumor-specific hyperthermia may help overcome resistance mechanisms to immunotherapy in advanced HCC.

Enhanced efficacy of direct immunochemotherapy for hepatic cancer with image-guided intratumoral radiofrequency hyperthermia

“…34 Some previous studies demonstrated that hyperthermia has immunomodulatory effects, 35 36 increases anticancers drug concentration in tumor cells, 37 38 and overcomes resistance mechanisms to immunotherapy in HCC. 33 The results of our study indicated RFH could enhance the immunotherapy for HCC.…”

“…Immunotherapy is a promising treatment method for HCC, but there are some barriers to immunotherapy for HCC, such as an immunosuppressive microenvironment. 33 Although immunotherapy has been shown to be effective in HCC, the response rates remain relatively low. For example, the CheckMate 459 trial, a randomized, open-label, multicenter, phase 3 trial study of an antiprogrammed cell death protein-1 checkpoint inhibitor (nivolumab) versus sorafenib for patients with advanced HCC, demonstrated an objective response rate of only 14% in the group of nivolumab treatment, and nivolumab treatment did not significantly improve overall survival compared with sorafenib.…”

Research progress of targeted therapy combined with immunotherapy for hepatocellular carcinoma

“…Molecularly targeted drugs reduce VEGF-mediated immunosuppression in tumors and their microenvironment and enhance the efficacy of anti-PD-1 and anti-PD-L1 by reversing VEGF-mediated immunosuppression and promoting intra-tumor T-cell infiltration, thereby enhancing the efficacy of immune checkpoint inhibitors ( 41 , 42 ), Molecularly targeted drugs combined with immune checkpoint inhibitors have additive or synergistic antitumor effects, and therefore targeted combination with immunization may be an effective treatment in unresectable HCC ( 43 , 44 ).…”

Interventional Oncolytic Immunotherapy with LTX-315 for Residual Tumor after Incomplete Radiofrequency Ablation of Liver Cancer

“…The heat-sink effect during RFA often results in a sublethal RFH at the ablated tumor margin. Previous studies reported that hyperthermia could increase the concentration of anti-cancer drugs in tumor cells [ 19 , 20 ], regulate the immune microenvironment [ 21 ], and overcome resistance mechanisms to immunotherapy in HCC [ 22 ]. Based on these reports, we delivered the oncolytic peptide of LTX-315 to the ablated tumor margin during RFA.…”