Tagliamonte Maria, Petrizzo Annacarmen, Napolitano Maria, Luciano Antonio, Rea Domenica, Barbieri Antonio, Arra Claudio, Maiolino Piera, Tornesello Marialina, Ciliberto Gennaro, Buonaguro Franco M, Buonaguro Luigi
Laboratory of Molecular Biology and Viral Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy.
Laboratory of Clinical Immunology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione Pascale" - IRCCS, Naples, Italy.
J Transl Med. 2016 Feb 24;14:58. doi: 10.1186/s12967-016-0812-1.
The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response.
In the present study, the counterbalance effect of a novel metronomic chemotherapy protocol on such an immunosuppressive microenvironment was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. The chemotherapy consisted of a novel multi-drug cocktail including taxanes and alkylating agents, administered in a daily metronomic fashion. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious.
Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4(+) T cell reduction and CD8(+) T cell increase. Furthermore, a significant reduction in the percentage of both CD25(+)FoxP3(+) and CD25(+)CD127(low) regulatory T cell population was found both in the spleens and in the tumor lesions. Finally, the metronomic chemotherapy induced an intrinsic CD8(+) T cell response specific to B16 naturally expressed Trp2 TAA.
The novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment. Consequently, the intrinsic anti-tumor T cell immunity could exert its function, targeting specific TAA and significantly containing tumor growth. Overall, the results show that this represents a promising adjuvant approach to significantly enhance efficacy of intrinsic or vaccine-elicited tumor-specific cellular immunity.
肿瘤免疫抑制微环境是有效诱导肿瘤特异性细胞免疫应答的主要障碍。
在本研究中，通过皮下异位植入B16黑色素瘤细胞建立小鼠模型，评估一种新型节拍化疗方案对这种免疫抑制微环境的平衡作用。化疗采用一种新型多药联合方案，包括紫杉烷类和烷化剂，以每日节拍给药方式进行。新设计的策略显示出安全、耐受性良好且显著有效。
与对照组相比，接受治疗的动物肿瘤生长明显延迟，生存期延长。这种效果与CD4(+) T细胞减少和CD8(+) T细胞增加直接相关。此外，在脾脏和肿瘤病灶中均发现CD25(+)FoxP3(+)和CD25(+)CD127(低)调节性T细胞群体的百分比显著降低。最后，节拍化疗诱导了针对B16自然表达的Trp2肿瘤相关抗原（TAA）的内源性CD8(+) T细胞应答。
本研究中评估的新型多药每日节拍化疗在平衡免疫抑制性肿瘤微环境方面非常有效。因此，内源性抗肿瘤T细胞免疫可以发挥其功能，靶向特定TAA并显著抑制肿瘤生长。总体而言，结果表明这是一种有前景的辅助方法，可显著提高内源性或疫苗诱导的肿瘤特异性细胞免疫的疗效。
