Yan Lisa, Da Silva Diane M, Verma Bhavna, Gray Andrew, Brand Heike E, Skeate Joseph G, Porras Tania B, Kanodia Shreya, Kast W Martin
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
Prostate. 2015 Feb 15;75(3):280-91. doi: 10.1002/pros.22914. Epub 2014 Nov 14.
LIGHT, a ligand for lymphotoxin-β receptor (LTβR) and herpes virus entry mediator, is predominantly expressed on activated immune cells and LTβR signaling leads to the recruitment of lymphocytes. The interaction between LIGHT and LTβR has been previously shown to activate immune cells and result in tumor regression in a virally-induced tumor model, but the role of LIGHT in tumor immunosuppression or in a prostate cancer setting, where self antigens exist, has not been explored. We hypothesized that forced expression of LIGHT in prostate tumors would shift the pattern of immune cell infiltration toward an anti-tumoral milieu, would inhibit T regulatory cells (Tregs) and would induce prostate cancer tumor associated antigen (TAA) specific T cells that would eradicate tumors.
Real Time PCR was used to evaluate expression of forced LIGHT and other immunoregulatory genes in prostate tumors samples. For in vivo studies, adenovirus encoding murine LIGHT was injected intratumorally into TRAMP-C2 prostate cancer cell tumor bearing mice. Chemokine and cytokine concentrations were determined by multiplex ELISA. Flow cytometry was used to phenotype tumor infiltrating lymphocytes and expression of LIGHT on the tumor cell surface. Tumor-specific lymphocytes were quantified via ELISpot assay. Treg induction and Treg suppression assays determined Treg functionality after LIGHT treatment.
LIGHT in combination with a therapeutic vaccine, PSCA TriVax, reduced tumor burden. LIGHT expression peaked within 48 hr of infection, recruited effector T cells that recognized mouse prostate stem cell antigen (PSCA) into the tumor microenvironment, and inhibited infiltration of Tregs. Tregs isolated from tumor draining lymph nodes had impaired suppressive capability after LIGHT treatment.
Forced LIGHT treatment combined with PSCA TriVax therapeutic vaccination delays prostate cancer progression in mice by recruiting effector T lymphocytes to the tumor and inhibiting Treg mediated immunosuppression. Prostate 75:280-291, 2015. © 2014 Wiley Periodicals, Inc.
LIGHT是淋巴毒素-β受体（LTβR）和疱疹病毒进入介质的配体，主要在活化的免疫细胞上表达，且LTβR信号传导会导致淋巴细胞募集。先前已表明LIGHT与LTβR之间的相互作用可激活免疫细胞，并在病毒诱导的肿瘤模型中导致肿瘤消退，但尚未探讨LIGHT在肿瘤免疫抑制或存在自身抗原的前列腺癌环境中的作用。我们假设在前列腺肿瘤中强制表达LIGHT会使免疫细胞浸润模式转向抗肿瘤微环境，抑制调节性T细胞（Tregs），并诱导能根除肿瘤的前列腺癌肿瘤相关抗原（TAA）特异性T细胞。
采用实时定量PCR评估前列腺肿瘤样本中强制表达的LIGHT及其他免疫调节基因的表达。在体内研究中，将编码小鼠LIGHT的腺病毒瘤内注射到携带TRAMP-C2前列腺癌细胞肿瘤的小鼠体内。通过多重ELISA测定趋化因子和细胞因子浓度。利用流式细胞术对肿瘤浸润淋巴细胞进行表型分析，并检测肿瘤细胞表面LIGHT的表达。通过ELISpot测定法对肿瘤特异性淋巴细胞进行定量。Treg诱导和Treg抑制试验确定LIGHT处理后Treg的功能。
LIGHT与治疗性疫苗PSCA TriVax联合使用可减轻肿瘤负担。LIGHT表达在感染后48小时内达到峰值，将识别小鼠前列腺干细胞抗原（PSCA）的效应T细胞募集到肿瘤微环境中，并抑制Tregs浸润。从肿瘤引流淋巴结分离的Tregs在LIGHT处理后抑制能力受损。
强制LIGHT治疗与PSCA TriVax治疗性疫苗联合使用可通过将效应T淋巴细胞募集到肿瘤中并抑制Treg介导的免疫抑制来延缓小鼠前列腺癌进展。《前列腺》75:280 - 291，2015年。©2014威利期刊公司。
