Kos Kevin, Salvagno Camilla, Wellenstein Max D, Aslam Muhammad A, Meijer Denize A, Hau Cheei-Sing, Vrijland Kim, Kaldenbach Daphne, Raeven Elisabeth A M, Schmittnaegel Martina, Ries Carola H, de Visser Karin E
Division of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Oncode Institute, Utrecht, The Netherlands.
Oncoimmunology. 2022 Apr 15;11(1):2063225. doi: 10.1080/2162402X.2022.2063225. eCollection 2022.
While regulatory T cells (T) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of T by promoting the conversion of conventional CD4 T cells (T) into T. Mechanistically, two processes were identified that independently contribute to this process. While TAM-derived TGF-β directly promotes the conversion of CD4 T into T, we additionally show that TAMs enhance PD-1 expression on CD4 T cells. This indirectly contributes to the intratumoral accumulation of T, as loss of PD-1 on CD4 T abrogates intratumoral conversion of adoptively transferred CD4 T into T. Combined, this study provides insights into the complex immune cell crosstalk between CD4 T cells and TAMs in the tumor microenvironment of breast cancer, and further highlights that therapeutic exploitation of macrophages may be an attractive immune intervention to limit the accumulation of T in breast tumors.
虽然调节性T细胞（Treg）和巨噬细胞已被公认为癌症相关免疫抑制的关键协调者，但它们在肿瘤内的细胞间相互作用却鲜有描述。在此，我们利用乳腺癌自发模型证明，肿瘤相关巨噬细胞（TAM）通过促进常规CD4 T细胞（Th）转化为Treg，促进了Treg在肿瘤内的积累。从机制上来说，我们确定了两个独立促成这一过程的机制。虽然TAM衍生的转化生长因子-β（TGF-β）直接促进CD4 Th细胞转化为Treg，但我们还表明，TAM会增强CD4 T细胞上程序性死亡受体1（PD-1）的表达。这间接促成了Treg在肿瘤内的积累，因为CD4 T细胞上PD-1的缺失消除了过继转移的CD4 Th细胞在肿瘤内转化为Treg的过程。综合来看，本研究深入探讨了乳腺癌肿瘤微环境中CD4 T细胞与TAM之间复杂的免疫细胞相互作用，并进一步强调，对巨噬细胞进行治疗性利用可能是一种有吸引力的免疫干预手段，可限制Treg在乳腺肿瘤中的积累。
