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Page 10 of 14 Monge Bonilla et al. Hepatoma Res 2020;6:68 I http://dx.doi.org/10.20517/2394-5079.2020.58

illumination of the effect of the gastrointestinal tract microbiome in HCC [112] , novel strategies in
combination with antimicrobial therapy might be part of future treatment regimens (NCT03785210), such
as chemotherapy, targeted therapy and radiation.

The overall clinical response to cell-based immunotherapy has not been robust, which indicates that
this therapy may be more helpful when there is a lower disease burden or these precisely designed cells
need to be used concurrently with other therapies in order to control HCC, e.g., in combination with
ICIs. Moreover, there are subtle but substantial aspects of cell-based immunotherapy that need further
evaluation, including virus antigen specific TCR therapy. A further example requiring better understanding
is the mechanism by which trafficking of CAR-T cells into HCC cells to execute anti-tumour effects in situ
can be achieved. This is a distinct problem observed in solid tumours that is not encountered in CAR-T
technology in haematological malignancies.

Lastly, since the overall response to immunotherapy in HCC is suboptimal, it would be critical to identify
responder candidates before treatment begins in order to improve the outcomes in patients with HCC
associated with HBV or HCV infection. Though tumour mutation burden, PD-L1 expression, TILs, IFN
signature and circulating tumour DNA have been indicated as predicative markers in other types of
tumours, there has not been strong evidence showing that these markers are valuable in HCC. Therefore,
further efforts to identify the predictive biomarkers that may help guide the selection of patients with HCC
who are appropriate for ICIs are needed, such as microbiome and TCR repertoire targets. Along with this,
intelligent, correlative studies from paired tumour biopsies will be helpful to identify the best therapeutic
approaches, timing, and sequences, and improve outcomes of patients with HCC.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception: Monge Bonilla C, Xie C
Manuscript writing and organizing, collect data and interpretation: Monge Bonilla C, McGrath NA, Fu J,
Xie C

Availability of data and materials
Not applicable.

Financial support and sponsorship
Xie C was supported by NIH/NCI/CCR Physician-Scientist Early Investigator Program (ZIA BC 011888).

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2020.

REFERENCE
1. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006;3:e442.