Crome Sarah Q, Nguyen Linh T, Lopez-Verges Sandra, Yang S Y Cindy, Martin Bernard, Yam Jennifer Y, Johnson Dylan J, Nie Jessica, Pniak Michael, Yen Pei Hua, Milea Anca, Sowamber Ramlogan, Katz Sarah Rachel, Bernardini Marcus Q, Clarke Blaise A, Shaw Patricia A, Lang Philipp A, Berman Hal K, Pugh Trevor J, Lanier Lewis L, Ohashi Pamela S
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Department of Microbiology and Immunology and the Parker Institute for Cancer Immunotherapy, University of California San Francisco, San Francisco, California, USA.
Nat Med. 2017 Mar;23(3):368-375. doi: 10.1038/nm.4278. Epub 2017 Feb 6.
Antitumor T cells are subject to multiple mechanisms of negative regulation. Recent findings that innate lymphoid cells (ILCs) regulate adaptive T cell responses led us to examine the regulatory potential of ILCs in the context of cancer. We identified a unique ILC population that inhibits tumor-infiltrating lymphocytes (TILs) from high-grade serous tumors, defined their suppressive capacity in vitro, and performed a comprehensive analysis of their phenotype. Notably, the presence of this CD56CD3 population in TIL cultures was associated with reduced T cell numbers, and further functional studies demonstrated that this population suppressed TIL expansion and altered TIL cytokine production. Transcriptome analysis and phenotypic characterization determined that regulatory CD56CD3 cells exhibit low cytotoxic activity, produce IL-22, and have an expression profile that overlaps with those of natural killer (NK) cells and other ILCs. NKp46 was highly expressed by these cells, and addition of anti-NKp46 antibodies to TIL cultures abrogated the ability of these regulatory ILCs to suppress T cell expansion. Notably, the presence of these regulatory ILCs in TIL cultures corresponded with a striking reduction in the time to disease recurrence. These studies demonstrate that a previously uncharacterized ILC population regulates the activity and expansion of tumor-associated T cells.
抗肿瘤T细胞受到多种负调控机制的影响。近期关于先天性淋巴细胞（ILC）调节适应性T细胞反应的研究结果促使我们研究ILC在癌症背景下的调节潜力。我们鉴定出一种独特的ILC群体，其可抑制高级别浆液性肿瘤中的肿瘤浸润淋巴细胞（TIL），在体外确定了它们的抑制能力，并对其表型进行了全面分析。值得注意的是，TIL培养物中这种CD56CD3群体的存在与T细胞数量减少有关，进一步的功能研究表明该群体抑制TIL扩增并改变TIL细胞因子的产生。转录组分析和表型特征确定调节性CD56CD3细胞具有低细胞毒性活性，产生IL-22，并且其表达谱与自然杀伤（NK）细胞和其他ILC的表达谱重叠。这些细胞高表达NKp46，向TIL培养物中添加抗NKp46抗体可消除这些调节性ILC抑制T细胞扩增的能力。值得注意的是，TIL培养物中这些调节性ILC的存在与疾病复发时间的显著缩短相对应。这些研究表明，一种先前未被表征的ILC群体可调节肿瘤相关T细胞的活性和扩增。
