Faluyi O O, Fitch P, Howie S E M
Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK.
MRC Centre for Inflammation Research, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
Clin Exp Immunol. 2018 Jan;191(1):32-41. doi: 10.1111/cei.13055. Epub 2017 Oct 24.
Only mismatch repair (MMR)-deficient colorectal cancer (CRC) appears to respond well to programmed death (PD)-1 inhibition at the present time. Emerging evidence suggests a role for micro-environmental factors such as CD25 cells modulating response to PD-1 inhibition. In the Apc model of familial adenomatous polyposis (MMR-proficient CRC), increased Cyclooxygenase-2 (Cox-2) expression by cells which include alternatively activated mononuclear phagocytes promotes intestinal tumorigenesis by mechanisms which may include immune suppression. To gain insight into this, we compared regulatory T cell (T ) populations between Apc and wild-type mice prior to and after the phase of increased intestinal Cox-2-dependent prostaglandin E (PGE ) production. There was no difference in systemic T function or numbers between Apc and wild-type mice. However, increased numbers of small intestinal CD25 T were observed with increased Cox-2 activity in the absence of any difference in the expression of Tgf-β or Tslp between Apc and wild-type mice. Cox-2 inhibitor therapy (Celecoxib) reversed the increase in Apc intestinal CD25 T numbers, without decreasing numbers of CD25 systemic T . Forkhead box protein 3 (FoxP3 ) and Cox-2 cells were co-localized to the interstitium of adenomas of Apc mice. These results suggest selective dependence of an 'activated T ' phenotype on paracrine Cox-2 activity in Apc small intestine. For therapeutic potential, further studies are required to evaluate the relevance of these findings to human cancer as well as the functional significance of CD25 intestinal T in cancer.
目前看来，只有错配修复（MMR）缺陷型结直肠癌（CRC）对程序性死亡（PD）-1抑制表现出良好反应。新出现的证据表明，诸如CD25细胞等微环境因素在调节对PD-1抑制的反应中发挥作用。在家族性腺瘤性息肉病的Apc模型（MMR功能正常的CRC）中，包括交替激活的单核吞噬细胞在内的细胞中环氧合酶-2（Cox-2）表达增加，通过可能包括免疫抑制的机制促进肠道肿瘤发生。为深入了解这一点，我们比较了Apc小鼠和野生型小鼠在肠道Cox-2依赖性前列腺素E（PGE）产生增加阶段之前和之后的调节性T细胞（T）群体。Apc小鼠和野生型小鼠在全身T功能或数量上没有差异。然而，在Apc小鼠和野生型小鼠之间Tgf-β或Tslp表达没有任何差异的情况下，随着Cox-2活性增加，观察到小肠CD25 T细胞数量增加。Cox-2抑制剂治疗（塞来昔布）逆转了Apc小鼠肠道CD25 T细胞数量的增加，而没有减少全身CD25 T细胞数量。叉头框蛋白3（FoxP3）和Cox-2细胞共定位于Apc小鼠腺瘤的间质。这些结果表明，“活化T”表型对Apc小肠中旁分泌Cox-2活性具有选择性依赖性。对于治疗潜力，需要进一步研究来评估这些发现与人类癌症的相关性以及癌症中CD25肠道T细胞的功能意义。
