Microwave ablation enhances tumor-specific immune response in patients with hepatocellular carcinoma

Abstract

Thermal ablative therapies are standard treatments for localized hepatocellular carcinoma (HCC). In addition to local tumor destruction, ablation leads to abscopal effects in distant lesions most likely mediated by an anti-tumor immune response. Although microwave ablation (MWA) is increasingly substituting other ablative techniques, its systemic immunostimulatory effects are poorly studied. We analyzed tumor-specific immune responses in peripheral blood of HCC patients after thermal ablation with regard to T cell responses and disease outcome. While comprehensive flow cytometric analyses in sequential samples of a prospective patient cohort (n = 23) demonstrated only moderate effects of MWA on circulating immune cell subsets, fluorospot analyses of specific T cell responses against seven tumor-associated antigens (TTAs) revealed de-novo or enhanced tumor-specific immune responses in 30% of patients. This anti-tumor immune response was related to tumor control as Interferon-y and Interleukin-5 T cell responses against TAAs were more frequent in patients with a long-time remission (> 1 year) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients) and presence of tumor-specific T cell response (IFN-y and/or IL-5) was associated to longer progression-free survival (27.5 vs. 10.0 months). Digital image analysis of immunohistochemically stained archival HCC samples (n = 18) of patients receiving combined MWA and resection revealed a superior disease-free survival of patients with high T cell abundance at the time of thermal ablation (37.4 vs. 13.1 months). Our data demonstrates remarkable immune-related effects of MWA in HCC patients and provides additional evidence for a combination of local ablation and immunotherapy in this challenging disease.

Immunological Effects of Histotripsy for Cancer Therapy

“…Studies that show an increase in tumor specific lymphocytes in secondary lymphoid organs or in peripheral blood have also established the correlation between these activated cells and systemic decreases in tumor burden (28)(29)(30)(31). More recently, additional studies have also defined B cell activation, the maintenance of plasma cells, and even the generation of tumor specific antibodies following local tumor ablation and dendritic cell activation (29,31). For example, a study treating hepatocellular carcinoma with RFA reported that only 91 of the 178 patients that had a decreased neutrophil-to-lymphocyte ratio, which is an often used biomarker of systemic immune system activation, independently correlated to a significantly increased survival when compared to patients that did not see the increased ratio (32).…”

“…Once in the lymphoid tissues, the dendritic cells present the antigens through MHC class I or class II receptors to naïve CD4+ and CD8+ T cells, respectively, along with co-stimulation of CD28 with CD80/86. Studies that show an increase in tumor specific lymphocytes in secondary lymphoid organs or in peripheral blood have also established the correlation between these activated cells and systemic decreases in tumor burden (28)(29)(30)(31). More recently, additional studies have also defined B cell activation, the maintenance of plasma cells, and even the generation of tumor specific antibodies following local tumor ablation and dendritic cell activation (29,31).…”

Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

“…Microwave ablation in HCC patients leads to abscopal effects in distant lesions reflected by enhanced tumor antigen specific T cell IFN-γ production that correlated with long term survival. These studies provide additional evidence for the potential synergistic effect that could be achieved by combination of local ablation and immunotherapeutic strategies against this challenging disease [128]. The above studies indicate that immune cell therapy is effective in reducing the recurrence rate, which is typically high for HCC patients following curative treatment.…”

The Effects of Localized Heat on the Hallmarks of Cancer

“…[218,219] Higher temperatures have been suggested as more efficient at instigating anti-tumor immune responses as they are more prolific at inducing immunogenic cell death, [220] although in vivo studies have repeatedly confirmed that 42°C for 30 min is effective for inducing significant DAMP expression. [221][222][223] A number of reports have described adaptive responses with thermal ablation as a monotherapy via similar mechanisms to hyperthermia; [219,224] however, in the majority of cases, ablative therapies only achieve durable antitumor immune responses when applied in combination with immunotherapies. [218,225] Therefore, based on the literature described, adaptive immunity can indeed be induced by moderate hyperthermia and the HSP70 family appear to be one of the principal sources of this response.…”