The Clinical Observation Of NK/T-cell Lymphoma Patients Treated With Pembrolizumab And The Impacting Factor Of PD-L1 Expression

BackgroundNatural Killer T-Cell Lymphoma(NKTCL)is a subtype of non-Hodgkin's lymphoma.The incidence rate in China is much higher than in Western countries.NKTCL is a type of tumor with special morphology,immunophenotype and biological behavior.It is highly invasive and has a rapid disease progression.Until now,its pathogenesis and driving factors are still not clear,and there is no standard treatment plan.Traditional treatment methods are ineffective.The efficacy and prognosis are poor.As the role of the immune system in tumorigenesis and progression is gradually revealed,immunotherapy based on immune checkpoint blockers and adoptive cell therapy has shown great potential in the treatment of tumors.Studies have shown that tumor cells induce negative immune response through the PD-L1/PD-1 pathway and promote immune escape,which is one of the reasons for the poor efficacy and prognosis of NKTCL.As the role of the immune system in tumorigenesis and progression is gradually revealed,immunotherapy based on immune checkpoint blockers and adoptive cell therapy has shown great potential in the treatment of tumors.The research of PD-L1 expressed in NKTCL is limited.A small number of studies have found that PD-L1 is not only expressed in the HL cell line but also in tumor tissues.In addition,the PD-L1 expression rate is higher in invasive lymphoma(such as diffuse large B-cell lymphoma,peripheral T-cell lymphoma)than that of indolent lymphoma(such follicular lymphoma,nodular sclerosis type Hodgkin's lymphoma).The expression of PD-L1 in NKTCL tissues was negatively correlated with the distribution of tumor infiltrating T lymphocytes(TIL);the expression level of PD-L1 was positively correlated with stage,LDH and Ki-67 levels,and negatively correlated with IPI scores.These findings suggest that in NKTCL microenvironment,tumor cells may inhibit TIL activity or promote apoptosis through the PD-L1/PD-1 pathway,leading to immune escape of lymphoma cells.However,the factors that cause the increase of PD-L1 expression are still uncertain.Relevant literature shows that the region of chromosome 9p24.1 and the JAK-STAT pathway are associated with the high expression of PD-L1 in classical Hodgkin's lymphoma(cHL)and primary mediastinal large B-cell lymphoma(PMLBCL).The JAK2 gene is one of the members of the JAK family(including JAK1,JAK2,JAK3,and non-receptor protein tyrosine kinase 2),JAKs and various transmembrane cytokines and growth that play an important role in signal transduction in hematopoietic cells.The cytoplasmic portion of the factor receptor is related.The JAK2 gene is one of the members of the JAK family(including JAK1,JAK2,JAK3,and non-receptor protein tyrosine kinase 2),JAKs and various transmembrane cytokines and growth that play an important role in signal transduction in hematopoietic cells.Activated JAK2 has become an important target for myeloproliferative diseases,and it gradually plays an increasingly important role in solid tumors.This experiment is designed to explore whether similar mechanisms exist in NK/T cell lymphomas.Objects1.A retrospective analysis of 7 patients with relapsed and refractory NK/T cell lymphoma using the PD-1 inhibitor pembrolizumab was conducted to evaluate the efficacy and safety of pembrolizumab in this disease.2.The influencing factors of PD-L1 expression on NKTCL tumor cells were preliminarily explored by NK/T cell lymphoma cell lines SNK-6 and YTS.Methods1.The data of 7 patients with relapsed/refractory NK/T-cell lymphoma treated with pembrolizumab were collected from the Lymphoma Clinic of the First Affiliated Hospital of Zhengzhou University.The efficacy and safety of the drug were retrospectively analyzed.2.Cell culture: The cell strains were cultured in complete medium and placed in an incubator with a relative humidity of 95% at a temperature of 37°C and containing 5% CO2.Each 2-3 days was changed according to the condition of the cells or an appropriate amount of the culture medium was added.3.Whole genome sequencing and bioinformatics analysis of normal NK cells and NK/T cell lymphoma cell lines SNK-6 and YTS were performed.4.After applying JAK2 inhibitors,the expression of PD-L1 and JAK2-STAT3 pathway-related proteins was detected by Western Blot.5.Statistical analysis: Experimental data were analyzed using SPSS 21.0 statistical software.Measured data were expressed as mean ± standard deviation(?X±S).One-way ANOVA was used to analyze the differences between groups.P<0.05 indicated that the difference was statistically significant.Results1.A median of 4(range,2-18)cycles of pembrolizumab was administered.The overall response rate(ORR)was 57.1%(95% confidence interval [CI],18% to 90%),with a complete response(CR)occurring in 2(28.6%)patients and a partial response(PR)observed in 2(28.6%)patients.Most of the adverse events were grade I-II,demonstrating that pembrolizumab has good safety.2.Compared with normal NK cells,the 9p24.1 region in SNK-6 and YTS cells was predominantly amplified.After JAK2 inhibitors were used,the expression of JAK2-STAT3 pathway-related proteins was decreased,and PD-L1 expression was decreased.Conclusion1.The administration of 100 mg pembrolizumab every 3 weeks has certain effectiveness in the treatment of relapsed and refractory NK/T cell lymphoma,and the adverse events caused by the drug can be tolerated.2.The amplification of 9p24.1 region in NKTCL cell lines,inhibition of the JAK2-STAT3 pathway may directly or indirectly reduce the expression of PD-L1 in NKTCL.