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Table 5. Crucial immune checkpoint and risk alleles and their potential significance to the pathogenesis and treatment of NKTCL
The Potential
alterations of hallmark/signaling Role in pathogenic Ref. Potential treatment Ref.
human pathways mechanism of lymphoma significance
genetics
[80] [85]
Immune evasion PD-1/PD-L1 The combination of PD-1 and Iwai et al. PD-1/PD-L1 blockade therapies Kwong et al.
PD-L1 is one of the most applied to NKTCL have been Li et al. [86]
[89]
important pathways for developed or are ongoing, and Shen et al.
tumors to escape immune there are a few promising Lim et al. [87]
[88]
surveillance results Kim et al.
HLA risk alleles rs9277378 Exhibits the strong association Li et al. [15] Susceptible population N/A
with susceptibility of NKTCL screening and disease risk
stratification
[16]
rs13015714 Located at the IL18RAP region Lin et al. Identifying high risk population N/A
and involved in inflammation for targeted prevention
and immune regulation
[16]
rs9271588 Located at the HLA-DRB1 Lin et al. Identifying the high-risk N/A
region and involved in antigen population for targeted
presentation prevention
NKTCL: Extranodal natural killer/T cell lymphoma; PD-1/PD-L1: programmed death ligand-1/ programmed death-1; HLA: human leukocyte
antigen; IL18RAP: interleukin 18 receptor accessory protein; HLA-DRB1: major histocompatibility complex, class II, DR beta 1.

lymphoma pathogenesis [104-106] .

Immune cell therapies targeted EBV
Studies have proved that EBV is closely related to the pathogenesis of NKTCL. While exploring the relevant
molecular pathogenic mechanisms, scholars commit to explore the target of EBV for therapy. After 29 high-
risk or recurrent cases with EBV+ lymphoma received autologous LMP-cytotoxic T lymphocytes (CTLs)
therapy, 27 patients achieved CR . Similarly, allogeneic donor-derived LMP-specific T cells (LMP-Ts), as
[107]
an ancillary therapy, maintained the clinical response of EBV+ lymphoma patients who had underwent
allogeneic bone marrow transplantation, and the two-year OS of 26 patients was 68% . Noticeably, a
[108]
recent study reported that EBV-specific induced pluripotent stem cell-derived antigen-specific CTLs can
[109]
prompt enduring and strong antineoplastic activity . The above research implies that specific immune cell
therapies targeting EBV-related antigens are potential strategies. In the future, the safety and effectiveness of
cell therapy should be further verified in larger multi-center trials which may bring more clinical benefits to
NKTCL patients.

CONCLUSION
During the past decade, with the development of gene expression profiling and next-generation sequencing
technology, people have expanded the understanding of the functional structure of genes. This provides
novel perspectives for exploring the genetic mechanism of NKTCL and opportunities to develop new
therapeutic strategies for NKTCL patients. Up to now, PD-1/PD-L1 blockade therapy has undoubtedly been
an extremely noteworthy treatment option. As a novel regulator, CMTM6 regulates PD-L1 through
endosystemic circulation, and PD-L1 can be specifically reduced due to the deletion of CMTM6. This
discovery will be an interesting direction for further uncovering the NKTCL pathogenic mechanism .
[110]
Dysregulated signaling pathways are of noticeable significance in NKTCL and studies about related
inhibitors also brings potential targets for the treatment of NKTCL [45,46,52,58,59] . The intimate relationship
between EBV infection and NKTCL has been clearly proposed, and specific immune cell therapies targeting
EBV are being investigated. Nevertheless, the interaction mechanism between the EBV genome and the
human genome in NKTCL is yet to determined. As the results of various basic and clinical trials have been
reported, feasible targets and possible treatments of NKTCL have been proposed and further studied. To