Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma

Abstract

Radiofrequency ablation (RFA) is one of the treatments for hepatocellular carcinoma (HCC) and is known to enhance host immune response. However, the epitopes to which enhanced immune responses occur, the impact on patient prognosis, and the functions and phenotype of T cells induced are still unclear. To address these issues, we analyzed immune responses before and after RFA in 69 HCC patients using 11 tumor-associated antigen (TAA)-derived peptides that we identified to be appropriate to analyze HCC-specific immune responses. The immune responses were analyzed using enzyme-linked immunospot (ELISPOT) assay and tetramer assays using peripheral blood mononuclear cells. An increase in the number of TAA-specific T cells detected by interferon-c ELISPOT assays occurred in 62.3% of patients after RFA. The antigens and their epitope to which enhanced T cell responses occur were diverse, and some of them were newly induced. The number of TAA-specific T cells after RFA was associated with the prevention of HCC recurrence, and it was clarified to be predictive of HCC recurrence after RFA by univariate and multivariate analyses. The number of TAA-specific T cells after RFA was inversely correlated with the frequency of CD14 1 HLA-DR 2/low myeloid-derived suppressor cells (MDSCs). The modification of T cell phenotype was observed after RFA. The number of TAA-specific T cells at 24 weeks after RFA was decreased. Conclusion: Although RFA can enhance various TAA-specific T cell responses and the T cells induced contribute to the HCC recurrence-free survival of patients, besides immunosuppression by MDSCs, the memory phenotype and lifetime of TAA-specific T cells are not sufficient to prevent HCC recurrence completely. Additional treatments by vaccine or immunomodulatory drugs might be useful to improve the immunological effect of RFA. (HEPATOLOGY 2013; 57:1448-1457 H epatocellular carcinoma (HCC) is the sixth most frequent type of cancer worldwide, and it is becoming an important public health concern due to its increased incidence in Western and Asian countries. 1,2 Although there are many types of treatments for HCC, the posttreatment recurrence rate is very high. 3 To inhibit HCC recurrence and improve prognosis, an immunotherapeutic approach is considered an attractive strategy.Radiofrequency ablation (RFA) is one of the treatments for HCC and is now widely used for curative strategies. 4 In recent studies, it has been reported that

Myeloid-derived suppressor cells correlate with patient outcomes in hepatic arterial infusion chemotherapy for hepatocellular carcinoma

“…Increases have been reported in the frequency of TAA-specific T cells after treatments for HCC such as RFA and TACE [9,10]. In the present study, we found an MDSCs [11,12].…”

“…For example, HCC treatments with RFA or TACE were found to increase the frequency of tumor-associated antigen (TAA)-specific T cells due to the creation of an antigen source by the destruction of tumor cells [9,10]. In addition, recent studies demonstrated that beyond their direct cytotoxic effects on cancer cells, several conventional chemotherapeutic drugs promoted the elimination or inactivation of regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs), resulting in enhanced host antitumor immunity [11,12].…”

Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions

“…Patients with solitary lesions appear to have benefited more than patients with multiple lesions, which may be explained by the rapid pharmacokinetics of LTLD (19) along with prolonged RFA heating. Longer heating appears to increase local tissue concentration of doxorubicin released from LTLD (24) and heating may also trigger a local T-cell response (30). In patients with multiple lesions, the time needed to reposition the probe and initiate the ablation would lose the high serum concentration of LTLD due to relatively rapid clearance.…”

“…This limitation may explain why the addition of LTLD to RFA had no impact on outcomes in the overall population. Dexamethasone, which was administered in the LTLD arm to prevent type I hypersensitivity, could have blunted the postablation inflammatory and immune T-cell response (30). This could be particularly true in patients who did not receive a sufficient thermal dose and local LTLD release.…”

Synergistic Anti-Tumor Effects of Zoledronic Acid and Radiotherapy against Metastatic Hepatocellular Carcinoma

“…Radiotherapy can destroy cancer cells and enhance tumorassociated antigen presentation (14). However, radiotherapyinduced microenvironmental hypoxia also recruits proinflammatory cells, including TAMs and myeloid-derived suppressor cells (15,16), which can impair the anti-tumor attack enacted by NK or T cells and induce regulatory T cells (17)(18)(19).…”