RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:CD39(+) tumor infiltrating T cells from colorectal cancers exhibit dysfunctional phenotype.
CD39(+) tumor infiltrating T cells from colorectal cancers exhibit dysfunctional phenotype.
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近期研究显示,CD39在肿瘤特异性CD4+TIL(肿瘤浸润淋巴细胞)(TILs)中高表达。然而,CD39+T细胞在结直肠癌(CRC)中的功能差异仍有待阐明。
本研究分离了CRC患者和荷瘤小鼠的T细胞,以评估CD39在T细胞中的功能。我们发现,CRC患者瘤内T细胞中CD39升高,且与细胞因子分泌能力呈负相关。T细胞活化诱导CD39表达,且CD39+T细胞在响应CRC肿瘤抗原时产生更多IFN-γ。
此外,荷瘤小鼠脾脏中的CD39+T细胞在体外表现出比CD39-T细胞更强的抗肿瘤活性,但CD39-TILs与CD39+TILs之间的抗肿瘤活性无显著差异。
此外,我们发现CD39+T细胞表达更高的检查点分子,且比CD39-T细胞含有更高比例的Treg细胞,提示CD39+T细胞可能与免疫抑制表型相关。并且T细胞上的CD39表达可将促炎性eATP转化为免疫抑制性eADO。
然而,来自接种疫苗的野生型小鼠和CD39-/-小鼠的T细胞均能在体外识别并清除肿瘤细胞,且过继转移这些T细胞可抑制荷瘤小鼠的肿瘤生长。
总之,我们的研究揭示了CD39+T细胞的功能差异,这些细胞对肿瘤抗原具有反应性,但表现出功能障碍表型。
Recent studies revealed that CD39 was highly expressed in tumor-specific CD4 + tumor infiltrating lymphocytes (TILs).
However, the divergent function of CD39 + T cells remains to be elucidated in colorectal cancer (CRC). In this study, T cells from CRC patients and tumor-bearing mice were isolated to evaluate the function of CD39 in T cells.
We found that CD39 was elevated in intratumoral T cells from CRC patients, and negatively correlated with cytokine secretion capacity. T cell activation induced CD39 expression, and CD39 + T cells produced more IFN-γ in response to CRC tumor antigens.
In addition, CD39 + T cells in the spleens of tumor-bearing mice exhibited a stronger anti-tumor activity in vitro than CD39 - T cells, but there was no significant difference in the anti-tumor activities between CD39 - TILs and CD39 + TILs.
Moreover, we found that CD39 + T cells expressed higher checkpoint molecules and contained a higher proportion of Treg cells than CD39 - T cells, suggesting that CD39 + T cells may be correlated with an immunosuppressive phenotype. And CD39 expression on T cells could convert pro-inflammatory eATP to immunosuppressive eADO.
However, both T cells from the vaccinated-wild-type mice and CD39 -/- mice could recognize and eliminate tumor cells in vitro, and adoptive transfer of these T cells resulted in tumor growth inhibition in tumor-bearing mice.
In conclusion, our study revealed the divergent functions of CD39 + T cells, which were reactive to tumor antigen but exhibited a dysfunctional phenotype.
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