| Background and objective Blocking of programmed cell death receptor(PD-1)in immunotherapy can effe-ctively treat with several cancers.Several studies have shown that some immuno-therapy-related cytokines and T-cell subsets in peripheral blood are consistent wi-th the distribution of tissue-specific gene mutations,and it is possible to dynami-cally monitor immunotherapy biomarkers in peripheral blood.In this study,we ex-plored peripheral blood biomarkers related to the anti-PD-1 immune efficacy by dynamically detecting the peripheral blood biomarkers of tumor patients.Methods From November 2018 to October 2019,46 patients with advanced tumors whoreceived immunotherapy were drawn fasting venous blood before immunotherapy.20 healthy volunteers were selected as a control group.1.In this study,We analyzed the changes of IL-6,IL-8,IL-10,INF-γ in plasmaby Elisa,and detected peripheral blood LDH by AU5800 full-automatic enzyme l-abeling analysis.Its relationship with the short-term efficacy of immunotherapy was also analyzed.2.The expression of immune checkpoints on peripheral blood lymphocytes was detected by flow cytometry,and the distribution of immune cell subsets in perip-heral blood was analyzed with Ki-67 as an indicator of T cell activation.The cli-nical data of patients were collected,and the relationship between peripheral bl-ood biological indicators and recent curative effects was summarized.3.Circulating tumor DNA TMB was tested and consistent analyzed with the effi-cacy prediction of peripheral immune indicators.Results 1.Cancer patients had systemic inflammation before immunotherapy.The serum concentrations of IL-6 and CXCL-8 in the non-response group of anti-PD-1 imm-unotherapy were significantly higher than pre-treatment,which may indicate a p-oor prognosis.In the response group,INF-γ was higher than pre-treatment,and the amplitude was larger than that in the non-response group,indicating a better prognosis.However,the results needed to be further confirmed by expanding the samples.2.LDH was a potential circulating indicator of tumor burden.3.Ki-67+CD8+ T cells increased after 1 cycle of anti-PD-1 treatment,and then decreased in most patients.The increase of Ki-67 expression during treatment wasmost significant in PD-1+and PD-1-CD8+T cells(P<0.0001).Most tumor patients(30 of 46 patients)had a biologically significant increase in Ki-67 expression in PD-1+ CD8+ T cells after treatment.4.The responding Ki-67+ CD8+ T cell population was mainly CD45 RAlow CD27hi,containing cells that highly expressed CTLA-4,PD-1,2B4 and lowly expressed NKG2-D(P<0.0001).Ki-67 expression trend in CD8+ T cells expressing inhibitory receptors suggested that approximately 45% of PD-1+ CTLA-4+ cells express Ki-67 before treatment,and increased to approximately 69% after treatment.5.Higher tumor burden was associated with more Ki-67+CD8+T cells before andafter treatment,and this correlation became stronger after treatment.The maximum fold change in Ki-67 expression rate of PD-1+CD8+ T cells during the treatme-nt cycle was higher in the response group than in the non-response group(P<0.0001).6.Patients with longer PFS usually had lower tumor burden.Ki-67 expression to tumor burden ratio greater than 0.6 at 1st cycle of anti-PD-1 immunotherapy w-as associated with improvement of PFS(P<0.05).7.After one cycle of anti-PD-1 treatment,the plasma IFN-γ increased,which was consistent with the distribution of PD-1+CTLA-4+CD8+ T subgroup(P<0.0001).8.After one cycle of anti-PD-1 treatment,Ki67/LDH(%)(adjusted)greater than 1.5,Ki-67 expression(PD-1+CD127+CD4+ T cell)to tumor burden ratio greater than 0.5,CD8+CD45RO+/CD8+(%)greater than 40.2% may be related to PFS improvement(P<0.05).9.Ki-67+ /PD-1+CTLA-4+CD8+(%),Ki-67+ /TB(%)(PD-1+CD8+T Cell)were consistent with the predictive efficacy of b TMB in anti-PD-1 immune response,with Cohen’s kappa coefficients of 0.783 and 0.800,respectively.Conclusion 1.There is a systemic inflammation in tumor patients before immunotherapy.A certain degree of T cell invigoration may affect the trend changes of cytokines INF-γ,IL-6,CXCL-8,IL-10.The increase of cytokine INF-γ may indicate a good effect of anti-PD-1 immunotherapy;while the increase of cytokines CXCL-8 and IL-10 may indicate a poor effect.And further confirmation is needed.2.LDH may be a potential circulating indicator of tumor burden.3.Activation of circulating Tex cells before treatment related to tumor burden is associated with clinical efficacy.Circulating Tex cell subsets are clinically available potential predictors of anti-PD-1 immune efficacy.4.Patients with longer PFS usually have lower tumor burden,and the ratio of Tex cell invigoration to tumor burden may be related to clinical prognosis.5.Ki67/LDH(%)(adjusted),Ki-67 expression(PD-1+ CD127+ CD4+ T cell)to tumor burden ratio,CD8+CD45RO+/CD8+(%)may have certain predictive effe-cts on the efficacy of PD-1 immunotherapy.6.Immune indicators Ki-67+ /PD-1+CTLA-4+CD8+(%),Ki-67+ /TB(%)(PD-1+CD8+T Cell)were consistent with the predictive efficacy of b TMB in anti-PD-1 immune response. |
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