Page 171 - Read Online

Hjalgrim et al. J Transl Genet Genom 2022;6:134-46 https://dx.doi.org/10.20517/jtgg.2021.46 Page 140

utilize this to target the HRS cells. Secondly, gene expression profiling suggest that the TME composition
vary between EBV-positive and EBV-negative cHLs. Specifically, TME in EBV-positive cHLs is enriched for
[59]
genes related to T-cell and antiviral activity compared with EBV-negative cHL .

One attempted novel treatment strategy taking advantage of EBV’s presence in the HRS cells aims to induce
a lytic viral gene programme instead of the normal latency II pattern, which can be accomplished by, e.g.,
[60]
histone deacetylase inhibitors . At the same time as the change to expression of lytic viral antigens per se
should render the HRS cells more immunogenic to the host immune system, it would also provide a
window of opportunity for the use of antiviral agents. For cHL this treatment strategy is still in its infancy
and its full potential still to be established [61,62] .

Among the other modern treatment strategies two attract particular interest, T-cell therapy and immune
checkpoint blockade. These treatment approaches both depend on the effective presentation of antigens to
the immune system. As mentioned, HLA class I and II constitution both seem important to cHL risk, but
normal HLA-class I and HLA class II expression are commonly lost by the HRS cells, more so in EBV-
negative cHL than in EBV-positive cHL . Thus, Nijland et al. recently investigated 361 cHL cases and
[63]
[58]
reported HLA class I expression in 72.6% of EBV-positive cases as compared with 16.8% of EBV-negative
cases, and HLA class II expression in 70.3% of EBV-positive cases and 53.2% of EBV-negative cases. Besides
[63]
confirming previous reports of loss of HLA expression in HRS cells, Nijland et al. also established that
HLA class II expression would in effect be dysfunctional in many cases (38.8% of EBV-positive cases; 23.7%
of EBV-negative cases).

Most EBV-positive HRS cells therefore should be able to present both EBV-derived antigenic peptides and
neo-antigens and (therefore) also to elicit host immune-responses. The development of EBV-positive cHL is
therefore a testament to the effectiveness of the immune-evasive mechanisms evoked by the HRS cells .
[58]

Despite these tumour-related mechanisms Bollard et al. achieved good results with treatment with
[64]
autologous expanded LMP-cytotoxic T-lymphocyte infusions in a study of 50 patients with EBV-positive
lymphomas, half of which were cHLs.

Of the 25 patients with cHL with either active relapsing disease (n = 8) or in remission with high risk of
relapse (n = 17), only four patients - all of whom had active disease - did not respond to treatment. Thus, at
end of follow up 21 patients had achieved complete or sustained remission and were either free of cHL or
[64]
had died for other reasons (five patients) .
Noteworthy, three of the eight patients with active disease had cHLs expressing the EBV latency III pattern
typical of post-transplant lymphoproliferative diseases and all responded to treatment. In contrast, only one
of the remaining five patients who exhibited the typical EBV latency II pattern responded to treatment,
emphasizing the challenge of generating immune responses to latency type II antigens in HRS cells [64,65] .

The group has continued their efforts to develop more effective EBV-specific T-cell therapy by making the
T-cells resistant to the suppressive effect of TGF-β secreted by the TME. In a clinical trial including eight
patients with or at risk of cHL relapse, two complete and one partial response was observed in seven
patients who could be evaluated .
[66]