Cancer Research:中和酸性环境,免疫疗法可以更强
生物通/叶予 · 2016/03/22
癌细胞有能力在酸性的肿瘤环境中生长,而这种环境对免疫细胞是有害的。本周Cancer Research杂志的封面文章,Moffitt癌症中心的研究人员最近发现,中和酸性肿瘤环境可以提高癌症免疫疗法的效力,这项研究登上了本期Cancer Research杂志的封面。

癌细胞有能力在酸性的肿瘤环境中生长,而这种环境对免疫细胞是有害的。本周Cancer Research杂志的封面文章,Moffitt癌症中心的研究人员最近发现,中和酸性肿瘤环境可以提高癌症免疫疗法的效力,这项研究登上了本期Cancer Research杂志的封面。

实体瘤中的酸性环境会减弱许多免疫细胞的功能,改善自身的生存条件。肿瘤还能表达阻断免疫细胞的蛋白,避免被免疫系统发现。近年来人们开发了不少重新激活免疫系统的癌症疗法,包括靶标免疫抑制蛋白PD-1和CTLA-4的药物。虽然免疫疗法被视为癌症治疗的希望,但目前只有11% - 27%的患者响应这些药物。这说明癌症免疫疗法还需要进一步的改善。


研究人员随后证实,将碳酸氢钠与CTLA-4 或PD-1抑制剂结合起来,能更有效的抑制小鼠黑色素瘤和胰腺肿瘤的生长。碳酸氢钠也可以帮助特异性靶标肿瘤的T细胞,获得更高的治疗效率。

“肿瘤微环境的酸性pH有显著的免疫抑制效果。通过中和这种酸性,我们能够增强黑色素瘤和胰腺肿瘤对免疫疗法的应答,”文章通讯作者Robert J. Gillies博士说。研究人员正在计划招募胰腺癌和黑色素瘤患者,在临床试验中评估碳酸氢钠结合PD-1抑制剂的治疗效果。

  • Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

    Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation. Cancer Res; 76(6); 1381–90. ©2015 AACR.

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