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Jiang et al. J Transl Genet Genom 2021;5:323-40 https://dx.doi.org/10.20517/jtgg.2021.21 Page 333

[80]
1 and PD-L1 is one of the most important pathways for tumors to escape immune surveillance . PD-1/PD-
[81]
L1 blockade in various tumors, such as relapsed/refractory Hodgkin’s lymphoma , non-small-cell lung
[83]
[84]
cancer , melanoma , and colorectal cancer , has been verified to be a newly favorable treatment option
[82]
distinctive from traditional chemotherapeutics.
There are also studies on PD-1/PD-L1 blockade therapy applied to NKTCL patients. In the trial of
[85]
Kwong et al. , all patients responded for a long time, including two patients with CR, three patients
achieving clinical and radiological CR, and the rest with partial remission. Relapse/refractory NKTCL
patients who failed previous chemotherapies were treated with pembrolizumab, and the response was
favorable. Four out of seven patients responded to the treatment and the adverse effects were tolerable .
[86]
Whole-genome sequencing on 19 refractory/relapsed NKTCL patients receiving pembrolizumab showed
that the structural rearrangement of the PD-L1 gene (PD-L1 MUT ) disrupting the 3’-UTR was the only gene
variation in tumor samples of patient who had response to pembrolizumab in contrast with non-
responders. The somatic mutation was detected in 4/7 patients who completely responded to
pembrolizumab, but it was not seen in all non-responders. Besides, researchers revealed this mutation was
[87]
associated with better survival (P = 0.0279) . This may be a predictive response marker of PD-1/PD-L1
blockade therapy for NKTCL. As treatment for PD-L1 blocking therapy, a phase II clinical trial of avelumab
was reported that 21 NKTCL patients showed a CR rate of 24% (5/21) and an overall response rate of 38%
(8/21). The study also found patients with high PD-L1 expression levels had better treatment response .
[88]
A meta-analysis including 4174 cases of five types of advanced or metastatic tumors displayed that PD-
1/PD-L1 inhibitors are more effective than conventional chemotherapy, and the overall survival (OS) of
patients is significantly prolonged, whether PD-L1 positive or negative . Based on the above research
[89]
reports, PD-1/PD-L1 blockade is a promising molecular-targeted approach. It is necessary to further explore
how to improve the therapeutic effect and safety of PD-1/PD-L1 blockade therapy in NKTCL.

HLA risk alleles
A Japanese study containing 25 NKTCL cases and 303 control individuals reported that the frequency of
human leukocyte antigen (HLA)-A*0201 in NKTCL patients was significantly lower than the baseline
control population . However, genome-wide association study did not observe similar results, probably
[90]
due to the small sample size. Notably, Li et al. identified 51 single-nucleotide polymorphisms (SNPs)
[15]
associated with NKTCL that are mapped to the MHC region of chromosome 6. rs9277378 (located in HLA-
DPB1) exhibits the strongest association with susceptibility of NKTCL [P = 4.21 × 10 , odds ratio (OR) =
−19
1.84]. Afterwards, Lin et al. reported two novel NKTCL risk loci, the IL18RAP region on 2q12.1
[16]
(rs13015714; P = 2.83 × 10 , OR = 1.39) and the HLA-DRB1 region on 6p21.3 (rs9271588; P = 9.35 × 10 ,
−16
−26
OR = 1.53). The rs1420106-A variant that is highly correlated with rs13015714 can upregulate the expression
of IL18RAP, which may be conducive to the proliferation of tumor cells. In addition, a haplotype
association analysis showed that 47F-67I, a component of the antigen binding pocket of HLA-DRB1, was
associated with a reduced risk of NKTCL, and 47Y-67L was the opposite to 47F-67I for the genetic risk for
NKTCL .
[16]

Furthermore, a seven-SNP-based classifier was designed based on the seven SNPs that correlated to
WDR27, UMAD1, TENM2, LINC02463, KDM4C, FGD4, and FAM71A. It had better predictive accuracy
than clinicopathological risk variables on the survival of NKTCL patients. The combined application of the
seven-SNP-based classifier and clinicopathological risk factor should be more accurate for predicting the
prognosis of NKTCL patients .
[91]