Tumor eradication by hetIL-15 locoregional therapy correlates with an induced intratumoral CD103intCD11b+ dendritic cell population

Locoregional monotherapy with heterodimeric IL-15 (hetIL-15) in a triple-negative breast cancer (TNBC) orthotopic mouse model resulted in tumor eradication in 40% of treated mice, reduction of metastasis and induction of immunological memory against breast cancer cells. hetIL-15 re-shaped the tumor microenvironment by promoting the intratumoral accumulation of cytotoxic lymphocytes, conventional type 1 dendritic cells (cDC1s) and a DC population expressing both CD103 and CD11b markers. These CD103intCD11b+DCs share phenotypic and gene expression characteristics with both cDC1s and cDC2s, have transcriptomic profiles more similar to monocyte derived DCs (moDCs) and correlate with tumor regression. Therefore, hetIL-15, a cytokine directly affecting lymphocytes and inducing cytotoxic cells, has also an indirect rapid and significant effect on the recruitment of myeloid cells, initiating a cascade for tumor elimination through innate and adoptive immune mechanisms. The intratumoral CD103intCD11b+DC population induced by hetIL-15 may be targeted for the development of additional cancer immunotherapy approaches.在三阴性乳腺癌（TNBC）原位小鼠模型中，采用异二聚体IL-15（hetIL-15）进行局部区域单药治疗，可使40%的受试小鼠实现肿瘤根除，同时减少肿瘤转移并诱导针对乳腺癌细胞的免疫记忆。hetIL-15可重塑肿瘤微环境，促进细胞毒性淋巴细胞、1型常规树突状细胞（cDC1s）以及同时表达CD103和CD11b标志物的树突状细胞群在肿瘤内部的聚集。这类CD103intCD11b+树突状细胞兼具cDC1s与2型常规树突状细胞（cDC2s）的表型和基因表达特征，其转录组谱更接近单核细胞衍生树突状细胞（moDCs），且与肿瘤消退相关。因此，作为一种可直接作用于淋巴细胞并诱导细胞毒性细胞产生的细胞因子，hetIL-15还可对髓系细胞的招募产生间接且快速显著的影响，通过固有免疫和适应性免疫机制启动肿瘤清除级联反应。由hetIL-15诱导的肿瘤内CD103intCD11b+树突状细胞群，有望成为开发新型癌症免疫疗法的潜在靶向靶点。