Increasing Tumor Extracellular pH by an Oral Alkalinizing Agent Improves Antitumor Responses of Anti-PD-1 Antibody: Implication of Relationships between Serum Bicarbonate Concentrations, Urinary pH, and Therapeutic Outcomes
Increasing Tumor Extracellular pH by an Oral Alkalinizing Agent Improves Antitumor Responses of Anti-PD-1 Antibody: Implication of Relationships between Serum Bicarbonate Concentrations, Urinary pH, and Therapeutic Outcomes
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DOI：
10.1248/bpb.b21-00076
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发表时间：
2021-06-01
影响因子：
2
通讯作者：
Ishida, Tatsuhiro
中科院分区：
文献类型：
--
作者：
Ando, Hidenori;Emam, Sherif E.;Ishida, Tatsuhiro
酸性细胞外pH（pHe）是肿瘤微环境的特征。一些报告表明，增加pH可以改善免疫检查点抑制剂在鼠模型中的反应。为了增加pH，向小鼠长期施用碳酸氢钠（NaHCO 3）或柠檬酸/柠檬酸钾钠（KNa-cit）。据推测，碳酸氢根离子（HCO 3-），从这些碱化剂在体内产生，增加了肿瘤中的pH值，和过量的HCO 3-消除到尿液中增加尿pH值。然而，关于改变血清HCO 3-浓度、尿HCO 3-浓度和尿pH值对免疫疗法的治疗结果的影响的公开信息很少。在这项研究中，我们报告了口服NaHCO 3或KNa-cit增加了小鼠B16黑色素瘤模型对抗程序性细胞死亡-1（PD-1）抗体（一种免疫检查点抑制剂）的反应。此外，我们报告说，每天口服碱化剂增加血液中的HCO 3-浓度，相应的增加肿瘤的pH值。血清HCO 3-浓度也与尿HCO 3-浓度和尿pH值相关。尿pH值与抗PD-1抗体免疫治疗的抗肿瘤作用之间存在明确的关系。我们的研究结果表明，当与NaHCO 3和KNa-cit等碱化剂联合使用时，血液HCO 3-浓度（对应于肿瘤pH和尿液pH值）可能是预测免疫治疗剂临床结果的重要因素。
Acidic extracellular pH (pHe) is characteristic of the tumor microenvironment. Several reports suggest that increasing pHe improves the response of immune checkpoint inhibitors in murine models. To increase pHe, either sodium bicarbonate (NaHCO3) or citric acid/potassium-sodium citrate ( KNa-cit) was chronically administered to mice. It is hypothesized that bicarbonate ions (HCO3-), produced from these alkalinizing agents in vivo, increased pHe in the tumor, and excess HCO3- eliminated into urine increased urinary pH values. However, there is little published information on the effect of changing serum HCO3- concentrations, urinary HCO3- concentrations and urinary pH values on the therapeutic outcomes of immunotherapy. In this study, we report that oral administration of either NaHCO3 or KNa-cit increased responses to anti-programmed cell death-1 (PD-1) antibody, an immune checkpoint inhibitor, in a murine B16 melanoma model. In addition, we report that daily oral administration of an alkalinizing agent increased blood HCO3- concentrations, corresponding to increasing the tumor pHe. Serum HCO3- concentrations also correlated with urinary HCO3- concentrations and urinary pH values. There was a clear relationship between urinary pH values and the antitumor effects of immunotherapy with anti-PD-1 antibody. Our results imply that blood HCO3- concentrations, corresponding to tumor pHe and urinary pH values, may be important factors that predict the clinical outcomes of an immunotherapeutic agent, when combined with alkalinizing agents such as NaHCO3 and KNa-cit.