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Hafezi et al. Hepatoma Res 2020;6:23 I http://dx.doi.org/10.20517/2394-5079.2020.02 Page 5 of 7

FUTURE DIRECTIONS IN HBV-HCC T CELL THERAPY
Despite encouraging results from the initial trials of TCR-redirected T cell therapy in LT patients with HCC
relapses, there is still a clear need for improvement of such therapies. Multiple factors present in the LT
[32]
sera could have an impact on the outcome of TCR-T immunotherapy . The impact of such variables also
remains largely unexplored and needs to be addressed. One of the main obstacles of T cell therapy post-LT
[33]
is the pharmacological immunosuppression started after transplantation to prevent graft rejection . Long-
term maintenance immunosuppression typically achieved by Tacrolimus alone, or in combination with
mycophenolate mofetil continues throughout the patient’s life. These drugs were designed to broadly impair
T effector function, therefore potentially impacting the adoptively transferred HBV-specific TCR-T cells
in vivo. With regard to that, in vitro experiments in a 3D model clearly showed that the mTOR inhibitor,
[34]
Rapamycin, could impair TCR-redirected T cell migration and cytotoxicity . Engineering T cells to be
resistant to such drugs or using different subsets of T cells with inherent resistant features could allow
engineered TCR-T cells to function effectively even in the face of strong immunosuppression. For instance,
knock-down of FK506-binding protein 1a, tacrolimus-specific binding protein, markedly recovers T cell
function in the presence of clinically-relevant concentrations of Tacrolimus, therefore the same strategy
[35]
could be employed to develop drug-resistant TCR T cells for the treatment of LT with HBV-HCC relapses .
Furthermore, at this moment, only αβ TCR T cells are used to engineer therapeutic HBV-specific TCR T
cells. Alternatively, the desired αβ TCR can also be introduced into other immune cells to provide extra
benefits. For example, mucosal-associated invariant T cells are non-conventional T cells representing 20%-
45% of the liver T cell repertoire [36,37] . These cells express a high level of multi-drug resistant pump called
ATP-Binding cassette subfamily b member 1 (ABCB1) which allows mucosal-associated invariant T cells to
retain their function in the face of chemotherapeutic intervention [36,38] . This drug-resistant feature, together
with liver specificity make these cells a highly promising candidate for developing new therapeutic T cells for
the treatment of liver associated cancers. Altogether, developing drug-resistant therapeutic TCR T cells could
have the potential for clinical application in the treatment of HBV-HCC relapses after curative LT, where
immunotherapeutic TCR T-cell function can still be exerted in the presence of obligate immunosuppression.
In our opinion, implementing these immunosuppressive drug resistant armored -TCR T cells could improve
current immunotherapy outcomes in HBV-associated HCC relapses and would most likely increase survival
rates by slowing down tumor progression.

DECLARATIONS
Authors’ contributions
Wrote the manuscript: Hafezi M, Bertoletti A, Tan A

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by a Singapore Translational Research (STaR) investigator award [MOH-000019
(MOH_STaR17nov-001)] and by a National Research Foundation (Singapore) award (NRF-CRP17-2017-06).

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.