The inability of CD8⁺ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function–associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin cell-adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improved antitumor response. 7HP349 monotherapy had modest effects on anti–programmed death 1–resistant (anti–PD-1–resistant) tumors, whereas combinatorial treatment with anti–cytotoxic T lymphocyte–associated protein 4 (anti–CTLA-4) increased CD8⁺ Teff intratumoral sequestration and synergized in cooperation with neutrophils in inducing cancer regression. 7HP349 intratumoral CD8⁺ Teff enrichment activity depended on CXCL12. We analyzed gene expression profiles using RNA from baseline and on treatment tumor samples of 14 melanoma patients. We identified baseline CXCL12 gene expression as possibly improving the likelihood or response to anti–CTLA-4 therapies. Our results provide a proof-of-principle demonstration that LFA-1 activation could convert a T cell–exclusionary TME to a T cell–enriched TME through mechanisms involving cooperation with innate immune cells.

中文翻译：

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LFA-1 激活富集冷肿瘤模型中的肿瘤特异性 T 细胞并与 CTLA-4 阻断协同作用

CD8 ⁺效应 T 细胞 (Teffs) 无法到达肿瘤细胞是肿瘤对癌症免疫治疗产生耐药性的一个重要方面。这些细胞向肿瘤微环境 (TME) 的募集受整合素的调节，整合素是在 T 细胞上表达的粘附分子家族。在这里，我们展示了 7HP349，一种淋巴细胞功能相关抗原 1 (LFA-1) 和极晚激活抗原 4 (VLA-4) 整合素细胞粘附受体的小分子激活剂，促进了肿瘤的优先定位。对肿瘤的特异性 T 细胞和改善的抗肿瘤反应。7HP349 单一疗法对抗程序性死亡 1 （抗 PD-1 抗性）肿瘤有适度的影响，而与抗细胞毒性 T 淋巴细胞相关蛋白 4（抗 CTLA-4）的组合治疗增加了 CD8 ⁺Teff 瘤内隔离并与中性粒细胞协同诱导癌症消退。7HP349 瘤内 CD8 ⁺ Teff 富集活性取决于 CXCL12。我们使用来自基线的 RNA 和 14 名黑色素瘤患者的治疗肿瘤样本分析了基因表达谱。我们确定基线 CXCL12 基因表达可能提高抗 CTLA-4 疗法的可能性或反应。我们的结果提供了原理验证证明，即 LFA-1 激活可以通过涉及与先天免疫细胞合作的机制将 T 细胞排斥的 TME 转化为 T 细胞富集的 TME。