A modulatory effect of L-arginine supplementation on anticancer effects of chemoimmunotherapy in colon cancer-bearing aged mice.
A modulatory effect of L-arginine supplementation on anticancer effects of chemoimmunotherapy in colon cancer-bearing aged mice.
复制标题
补充 L-精氨酸对患有结肠癌的老年小鼠化学免疫疗法的抗癌作用的调节作用。
DOI：
10.1016/j.intimp.2022.109423
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Harada M.
中科院分区：
文献类型：
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作者：
Ishitobi K;Iida Y;Kotani H;Taniura T;Notsu Y;Tajima Y;Harada M.
骨髓源性抑制细胞（MDSC）和调节性T细胞（TCFs）在患癌的老年宿主中增加。MDSC中的精氨酸酶-I降解L-精氨酸，L-精氨酸是T细胞活化和增殖所需的氨基酸。本研究比较了5-氟尿嘧啶（5-FU）/奥沙利铂（L-OHP）和环磷酰胺（CP）对青年和老年结肠癌荷瘤小鼠的治疗效果。用5-FU/L-OHP和CP治疗同系年轻小鼠的CT 26和MC 38结肠癌，其抑制作用明显，而对老年小鼠的抑制作用减弱，而L-精氨酸单药治疗对老年小鼠无抑制作用。然而，抗程序性细胞死亡（PD）-1抗体和补充L-精氨酸的额外治疗增强了老年小鼠化学免疫治疗的效果，一些小鼠被治愈。在所有联合治疗期间，肿瘤特异性细胞毒性T淋巴细胞（CTL）从具有非进展性肿瘤的小鼠产生，但不从具有进展性肿瘤的小鼠产生。老年小鼠血浆L-精氨酸水平低于年轻小鼠，化疗倾向于降低老年小鼠血浆L-精氨酸水平。与年轻小鼠相比，CT 26荷瘤老年小鼠肿瘤组织中的MDSCs活性、MDSCs-I表达和单核细胞MDSCs的比例降低，而在MC 38荷瘤老年小鼠中观察到相反的结果。更重要的是，低剂量的L-精氨酸在体外可抑制肿瘤特异性CTL的诱导，而L-精氨酸在体内可促进CT 26组织中CTL的浸润。这些结果表明，化学免疫治疗在荷癌老年小鼠中的效果较差，但补充L-精氨酸可以通过其对肿瘤特异性CTL的作用来调节其治疗效果。
Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are increased in cancer-bearing aged hosts. Arginase-I in MDSCs degradesL-arginine, an amino acid required for T cell activation and proliferation. In this study, we compared the therapeutic efficacy of 5-fluorouracil (5-FU)/oxaliplatin (L-OHP) and cyclophosphamide (CP) between young and aged colon cancer-bearing mice. Therapy with 5-FU/L-OHP and CP significantly suppressed thein vivogrowth of CT26 and MC38 colon carcinomas in syngeneic young mice, whereas this effect was attenuated in aged mice.L-arginine monotherapy showed no effect in aged mice. However, additional therapy with anti-programmed cell death (PD)-1 antibody andL-arginine supplementation boosted the effect of chemoimmunotherapy in aged mice, and some mice were cured. During all combination therapy, tumor-specific cytotoxic T lymphocytes (CTLs) were generated from mice with non-progressing tumor, but not from those with progressing tumor. PlasmaL-arginine levels were lower in aged than young mice, and chemotherapy tended to decrease the plasmaL-arginine levels in aged mice. Compared to young mice, CT26-bearing aged mice decreased arginase activity, arginase-I expression, and the proportion of monocytic MDSCs in tumor tissues, whereas contrasting results were observed in MC38-bearing aged mice. Importantly, the induction of tumor-specific CTLs was impaired at lower doses ofL-argininein vitro, and the infiltration of CTLs into CT26 tissues after chemoimmunotherapy was promoted byL-arginine administrationin vivo. These results indicate that chemoimmunotherapy was less effective in cancer-bearing aged mice, but thatL-arginine supplementation can modulate its therapeutic efficacy via its effect on tumor-specific CTLs.