聚肌胞对活化早期T细胞PD-1表达的诱导及对黑色素瘤生长的抑制作用
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摘要
目的探讨活化早期阶段(脾组织内,未向靶器官迁移的)T细胞程序性死亡受体1(PD-1)表达情况。方法 6～8周龄C57BL/6小鼠随机分组后,以Poly I:C肽疫苗免疫,7天后获取小鼠脾细胞,观察Poly I:C对非特异性及特异性T细胞活化的影响,并检测特异性CD8~+T细胞表面PD-1表达。同时,通过敲除CD8细胞观察Poly I:C的抗肿瘤效应是否与CD8~+T细胞相关。结果小鼠经PolyI:C免疫后,脾组织内非特异性及特异性T细胞活化均显著增强;活化的特异性CD8~+T细胞虽高表达PD-1,但仍可合成T细胞功能性分子IFN-γ。此外,Poly I:C能显著抑制荷瘤小鼠黑色素瘤生长(P=0.0243),且该效应与CD8~+T细胞有关。结论 Poly I:C可以促进T细胞活化;活化早期的(脾组织内)T细胞虽高表达PD-1,但仍具有功能。
Objective To investigate the expression level of programmed cell death protein 1(PD-1)in T cells at the early stage of activation(T cells remained in spleen, before migration to target organ).Methods C57 BL/6 mice(6-8 weeks old) were immunized with Poly I:C peptide vaccine after randomly grouping. Mice spleen cells were harvested 7 days after immunization. The effects of Poly I:C on the activation of antigen specific or nonspecific T cells were evaluated. PD-1 expression on the antigen specific CD8+T cells was also detected. Furthermore, correlation between the anti-tumor effects of Poly I:C and CD8+T cells was assessed by CD8 cell knockout. Results Poly I:C significantly promoted the activation of antigen specific or nonspecific T cells in mice spleens. Although antigen specific T cells increased the expression of PD-1, they could still synthesize IFN-γ, a T cell functional marker. Meanwhile, Poly I:C significantly inhibited the growth of melanoma in vivo(P=0.0243), which was correlated with CD8+T cells. Conclusion Poly I:C could promote the activation of T cells; although, T cells at the early stage of activation(remained in spleen)enhanced the expression of PD-1, they are still functional.
Objective To investigate the expression level of programmed cell death protein 1(PD-1)in T cells at the early stage of activation(T cells remained in spleen, before migration to target organ).Methods C57 BL/6 mice(6-8 weeks old) were immunized with Poly I:C peptide vaccine after randomly grouping. Mice spleen cells were harvested 7 days after immunization. The effects of Poly I:C on the activation of antigen specific or nonspecific T cells were evaluated. PD-1 expression on the antigen specific CD8+T cells was also detected. Furthermore, correlation between the anti-tumor effects of Poly I:C and CD8+T cells was assessed by CD8 cell knockout. Results Poly I:C significantly promoted the activation of antigen specific or nonspecific T cells in mice spleens. Although antigen specific T cells increased the expression of PD-1, they could still synthesize IFN-γ, a T cell functional marker. Meanwhile, Poly I:C significantly inhibited the growth of melanoma in vivo(P=0.0243), which was correlated with CD8+T cells. Conclusion Poly I:C could promote the activation of T cells; although, T cells at the early stage of activation(remained in spleen)enhanced the expression of PD-1, they are still functional.
引文
[1]Pauken KE,Wherry EJ.Overcoming T cell exhaustion in infection and cancer[J].Trends Immunol,2015,36(4):265-76.
[2]Topalian SL,Hodi FS,Brahmer JR,et al.Safety,activity,and immune correlates of anti-PD-1 antibody in cancer[J].N Engl JMed,2012,366(26):2443-54.
[3]Chen L,Han X.Anti-PD-1/PD-L1 therapy of human cancer:past,present,and future[J].J Clin Invest,2015,125(9):3384-91.
[4]Tumeh PC,Harview CL,Yearley JH,et al.PD-1 blockade induces responses by inhibiting adaptive immune resistance[J].Nature,2014,515(7528):568-71.
[5]Salem ML,Diaz-Montero CM,El-Naggar SA,et al.The TLR3agonist poly(I:C)targets CD8+T cells and augments their antigen-specific responses upon their adoptive transfer into na?ve recipient mice[J].Vaccine,2009,27(4):549-57.
[6]Ngoi SM,Tovey MG,Vella AT.Targeting Poly I:C to the TLR3-independent pathway boosts effector CD8 T cell differentiation through IFNα/β[J].J Immunol,2008,181(11):7670-80.
[7]Ngiow SF,Young A,Jacquelot N,et al.A Threshold Level of Intratumor CD8+T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1[J].Cancer Res,2015,75(18):3800-11.
[8]Inozume T,Hanada K,Wang QJ,et al.Selection of CD8+PD-1+lymphocytes in fresh human melanomas enriches for tumorreactive T cells[J].J Immunother,2010,33(9):956-64.
[9]Gros A,Robbins PF,Yao X,et al.PD-1 identifies the patientspecific CD8+tumor-reactive repertoire infiltrating human tumors[J].J Clin Invest,2014,124(5):2246-59.
[10]Forte G,Rega A,Morello S,et al.Polyinosinic-polycytidylic acid acid limits tumor outgrowth in a mouse model of metastatic lung cancer[J].J Immunol,2012,188(11):5357-64.
[11]Truxova I,Pokorna K,Kloudova K,et al.Day 3 Poly(I:C)-activated dendritic cells generated in CellGro for use in cancer immunotherapy trials are fully comparable to standard Day 5DCs[J].Immunol Lett,2014,160(1):39-49.
[2]Topalian SL,Hodi FS,Brahmer JR,et al.Safety,activity,and immune correlates of anti-PD-1 antibody in cancer[J].N Engl JMed,2012,366(26):2443-54.
[3]Chen L,Han X.Anti-PD-1/PD-L1 therapy of human cancer:past,present,and future[J].J Clin Invest,2015,125(9):3384-91.
[4]Tumeh PC,Harview CL,Yearley JH,et al.PD-1 blockade induces responses by inhibiting adaptive immune resistance[J].Nature,2014,515(7528):568-71.
[5]Salem ML,Diaz-Montero CM,El-Naggar SA,et al.The TLR3agonist poly(I:C)targets CD8+T cells and augments their antigen-specific responses upon their adoptive transfer into na?ve recipient mice[J].Vaccine,2009,27(4):549-57.
[6]Ngoi SM,Tovey MG,Vella AT.Targeting Poly I:C to the TLR3-independent pathway boosts effector CD8 T cell differentiation through IFNα/β[J].J Immunol,2008,181(11):7670-80.
[7]Ngiow SF,Young A,Jacquelot N,et al.A Threshold Level of Intratumor CD8+T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1[J].Cancer Res,2015,75(18):3800-11.
[8]Inozume T,Hanada K,Wang QJ,et al.Selection of CD8+PD-1+lymphocytes in fresh human melanomas enriches for tumorreactive T cells[J].J Immunother,2010,33(9):956-64.
[9]Gros A,Robbins PF,Yao X,et al.PD-1 identifies the patientspecific CD8+tumor-reactive repertoire infiltrating human tumors[J].J Clin Invest,2014,124(5):2246-59.
[10]Forte G,Rega A,Morello S,et al.Polyinosinic-polycytidylic acid acid limits tumor outgrowth in a mouse model of metastatic lung cancer[J].J Immunol,2012,188(11):5357-64.
[11]Truxova I,Pokorna K,Kloudova K,et al.Day 3 Poly(I:C)-activated dendritic cells generated in CellGro for use in cancer immunotherapy trials are fully comparable to standard Day 5DCs[J].Immunol Lett,2014,160(1):39-49.