Intratumoral delivery of CCL25 enhances immunotherapy against triple-negative breast cancer by recruiting CCR9 ⁺ T cells

Abstract

CCR9+ T cells have an increased potential to be activated and therefore may mediate strong antitumor responses. Here, we found, however, that CCL25, the only chemokine for CCR9+ cells, is not expressed in human or murine triple-negative breast cancers (TNBCs), raising a hypothesis that intratumoral delivery of CCL25 may enhance antitumor immunotherapy in TNBCs. We first determined whether this approach can enhance CD47-targeted immunotherapy using a tumor acidity–responsive nanoparticle delivery system (NP-siCD47/CCL25) to sequentially release CCL25 protein and CD47 small interfering RNA in tumor. NP-siCD47/CCL25 significantly increased infiltration of CCR9+CD8+ T cells and down-regulated CD47 expression in tumor, resulting in inhibition of tumor growth and metastasis through a T cell–dependent immunity. Furthermore, the antitumor effect of NP-siCD47/CCL25 was synergistically enhanced when used in combination with programmed cell death protein–1/programmed death ligand-1 blockades. This study offers a strategy to enhance immunotherapy by promoting CCR9+CD8+ T cell tumor infiltration.

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…There are no data on the influence of CCL25 on the recruitment of cells cooperating in the development of a tumor or its participation in angiogenesis [ 297 ]. However, this chemokine may cause infiltration of the tumor by cytotoxic TIL exhibiting CCR9 expression, which has an anticancer effect [ 298 ]. There are also indications that CCL25 causes lymphangiogenesis because activation of the CCL25→CCR9 axis increases the expression of VEGF-C and VEGF-D on the non-small-cell lung cancer cells [ 292 ].…”

A novel prognostic risk score model based on immune-related genes in patients with stage IV colorectal cancer

“…CCR9/CCL25 also has an important role in tumor invasion and metastasis by promoting EMT in liver, non-small cell lung cancer, and breast cancer cell lines [ 36 , 37 ]. More interestingly, intratumoral delivery of CCL25 can enhance PD-L1/PD-1 antibody therapy against triple-negative breast cancer by recruiting CCR9+ T cells [ 38 ]. Regarding CCL28, recent studies have found that blocking of β-catenin–CCL28 can reduce Treg cell infiltration and inhibit tumor growth.…”

Combined Application of Nanotechnology and Multiple Therapies with Tumor Immune Checkpoints

“…The study of Chen et al showed that the combined applications of NP-CCL25/ siCD47-induced immunotherapy and PD-L1/PD-1 blocker could synergistically enhance the anti-tumor effect. [33] Wang et al established a biochemical orthogonal system in which phenylalanine trifluoroborate (Phe-BF3) enters the cell as a tumor imaging probe and "cuts" the silyl ether, thereby removing the cell Silicon, so that the system can control the release of drugs in mice. When nanoparticles are combined with the design for delivery, Phe-BF3 catalyzed desalinization can release guest protein from the nanoparticle conjugate and selectively release the protein into tumor cells, thereby causing tumor regression and enhancing the anti-tumor immune response.…”