Integrins α1β1 (CD49a), α2β1 (CD49b) and αEβ7 (CD103) mediate retention of lymphocytes in peripheral tissues, and their expression is upregulated on tumor infiltrating lymphocytes (TIL) compared to circulating lymphocytes. Little is known about what induces expression of these retention integrins (RI) nor whether RI define subsets in the tumor microenvironment (TME) with a specific phenotype. Human metastatic melanoma-derived CD8 TIL could be grouped into five subpopulations based on RI expression patterns: RIneg, CD49a+ only, CD49a+CD49b+, CD49a+CD103+, or positive for all three RI. A significantly larger fraction of the CD49a+ only subpopulation expressed multiple effector cytokines, whereas CD49a+CD103+ and CD49a+CD49b+ cells expressed IFNγ only. RIneg and CD49a+CD49b+CD103+ CD8 TIL subsets expressed significantly less effector cytokines overall. Interestingly, however, CD49a+CD49b+CD103+ CD8 expressed lowest CD127, and highest levels of perforin and exhaustion markers PD-1 and Tim3, suggesting selective exhaustion rather than conversion to memory. To gain insight into RI expression induction, normal donor PBMC were cultured with T cell receptor (TCR) stimulation and/or cytokines. TCR stimulation alone induced two RI+ cell populations: CD49a single positive and CD49a+CD49b+ cells. TNFα and IL-2 each were capable of inducing these populations. Addition of TGFβ to TCR stimulation generated two additional populations; CD49a+CD49bnegCD103+ and CD49a+CD49b+CD103+. Taken together, our findings identify opportunities to modulate RI expression in the TME by cytokine therapies and to generate subsets with a specific RI repertoire in the interest of augmenting immune therapies for cancer or for modulating other immune-related diseases such as autoimmune diseases.

中文翻译：

---

人类转移性黑色素瘤中表达CD49a，CD49b和CD103的CD8 T细胞群体的形成和表型表征。

整合素α1β1（CD49a），α2β1（CD49b）和αEβ7（CD103）介导外周组织中的淋巴细胞滞留，与循环淋巴细胞相比，它们在肿瘤浸润淋巴细胞（TIL）中的表达上调。究竟是什么引起这些保留整联蛋白（RI）的表达，还是RI是否以特定表型定义了肿瘤微环境（TME）中的子集，人们所知甚少。根据RI表达模式，可将人类转移性黑色素瘤衍生的CD8 TIL分为五个亚群：RIneg，仅CD49a +，CD49a + CD49b +，CD49a + CD103 +或所有三个RI均为阳性。仅CD49a +的亚群中有很大一部分表达多种效应细胞因子，而CD49a + CD103 +和CD49a + CD49b +细胞仅表达IFNγ。RIneg和CD49a + CD49b + CD103 + CD8 TIL亚型总体表达的效应细胞因子明显更少。然而，有趣的是，CD49a + CD49b + CD103 + CD8表达最低的CD127，以及最高水平的穿孔素和力竭标志物PD-1和Tim3，表明选择性力竭而非转化为记忆。为了深入了解RI表达诱导，将正常供体PBMC与T细胞受体（TCR）刺激和/或细胞因子一起培养。单独的TCR刺激可诱导两个RI +细胞群体：CD49a单阳性和CD49a + CD49b +细胞。TNFα和IL-2均能够诱导这些群体。将TGFβ添加到TCR刺激中产生了另外两个种群。CD49a + CD49bnegCD103 +和CD49a + CD49b + CD103 +。在一起