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Immune changes linked to locoregional treatment of hepatocellular carcinoma

The landscape of therapeutic agents for hepatocellular carcinoma (HCC) is rapidly evolving, with the standard of care for patients with advanced disease now being the association of atezolizumab, an immunomodulator, and bevacizumab, an anti-angiogenic agent. Durable responses have been also observed with the immune checkpoint inhibitor nivolumab, and they may be preferentially observed for tumours with particular gene expression inflammatory signatures. The overall prognosis of patients, however, remains poor, and one of the next challenges to enhance the efficacy of immunotherapy will be to assess the benefits of its association with locoregional treatments (LRT), such as percutaneous ablation or transarterial chemo-embolisation (TACE). There is a strong scientific rationale supporting a synergistic effect of these different approaches: indeed, the cell death induced by LRT leads to the release of a significant amount of tumour-associated antigens that have the ability to further promote the recruitment and activation of T cells. In this line, LRT have been reported to induce a peripheral immune response in patients with HCC. Chemotherapy is also known to trigger a particular cell death, designated ‘immunogenic cell death’, that involves release of particular proteins [calreticulin and non-histone chromatin protein high-mobility group box 1 (HMGB1)], which facilitate the recruitment and activation of dendritic cells into the tumour microenvironment. This further allows the uptake of tumour antigens from dying tumour cells and an optimal antigen presentation to T cells. In this line, Duffy et al. showed that the combination of tremelimumab, an anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody, and LRT leads to the accumulation of intratumoral CD8 T cells in patients showing clinical benefit. Unfortunately, immune evasion mechanisms may hamper the activation of this antitumour immunity and thus explains relapse after treatment. Several trials assessing the efficacy of a TACE/immunotherapy combination in HCC patients are based on this hypothesis and are currently ongoing; however, data on the immune microenvironment of pretreated HCC samples are lacking. In this issue Monstasser et al. investigated, by means of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) immunohistochemistry, a series of surgically treated HCCs with and without pre-operative TACE. The study is particularly relevant, as doxorubicin, the most commonly administered drug in HCC chemoembolisation, is known to be one of the most potent inducers of immunogenic cell death. Consistent with previous studies, they first reported that the expression of PD-1 (≥ 1%) in inflammatory cells was observed in 46% of HCC, while the expressions of PD-L1 (≥ 1%) in inflammatory cells and tumour cells was observed in 46 and 16%, respectively. They further showed that HCCs in patients treated by TACE showed significantly higher PD-L1 expression in tumour cells than the tumours in untreated patients. Pretreatment biopsies were also available for a subset of samples and the authors were able to compare the effect of treatment for these cases, showing that PD-1 and PD-L1 expression was higher in TACE-treated tumours than in corresponding pre-TACE biopsies. For patients who did not receive TACE, there was no difference in PD-1 and PD-L1 expression in inflammatory cells or PD-L1 expression in tumour cells between the matched biopsy and surgical specimens. Altogether, this elegant study supports the hypothesis that TACE is able to induce an immunogenic cell death, leading to modifications of the intratumoral immune microenvironment. It provides an important rationale for the combination of TACE and immunotherapy in the treatment of HCC. An important issue will be to identifiy the patients most likely to benefit from this combination. Sangro et al. have shown that survival and overall response in patients with advanced HCC treated by nivolumab were associated with particular gene expression signatures and baseline tumour PD-1/ PD-L1 expression. The gene signatures included genes related to interferon gamma biology (CCL5, CD27, CXCL9, CXCR6, IDO1, STAT1), T cell exhaustion [CD274 (PD-L1), CD276, LAG3, PDCD1LG2, TIGIT] and antigen presentation (CMKLR1, HLADQA1, HLA-DRB1, PSMB10). It will now be critically important to investigate the relevance of these signatures on samples collected during the ongoing trials combining TACE and immunotherapy combination. The investigation of preand post-therapy biopsies, as performed in the study by Montasser et al., is also likely to provide important mechanistic information. Particular attention should also be paid to the histological appearance and the mutational profiles of the