Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model

Abstract

Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP(+) stromal cells which mimicked the FAP(+) CAF in vivo. We immunized a breast cancer mouse model with FAP(+) stromal cells to perform immunotherapy against FAP(+) cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP(+) stromal cells whose phenotype was CD11b(+)/CD34(+)/Sca-1(+)/FSP-1(+)/MHC class I(+). Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP(+) stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4(+) and CD8(+) T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP(+) CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP(+) stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

“…In this context, it is conceivable that surface markers expressed mainly, if not exclusively, by MSC should be considered to regulate the TME. Indeed, FAP, CD73, and CD105 can be considered as suitable markers to target MSC [11,13,14,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150]. In hematological malignancies, but also in solid tumors, the administration of immunomodulatory drugs (IMiDs) derived from their prototype Thalidomide to CC-122 has given very attractive results because these compounds can hit MSC besides tumor cells [151,152,153].…”

“…Several kinds, compositions, and modes of administration of anti-tumor vaccines have been used with different results [160,161,162,163,164,165,166,167]. More recently, the focus of anti-tumor vaccines has been moved from tumor cells to TME too [7,9,10,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175]. Indeed, the possibility of targeting tumor endothelial cells or the VEGF signaling axis with specific vaccines has been assessed in preclinical studies, and clinical trials are ongoing [168].…”

Abrogation of myofibroblast activities in metastasis and fibrosis by methyltransferase inhibition

“…With these observations in mind, interfering with CAF activity has been envisioned as an antimetastatic pharmacological strategy . A phase I study showed that the gelatinase FAP expressed in CAFs selectively accumulates in the tumor area, and that vaccination with FAP+ stromal cells significantly inhibits the growth of allograft tumors and reduces lung metastasis in a breast cancer‐bearing mouse model . These results support the idea that developing anti‐CAF reagents would interfere with tumor malignancy in breast cancer.…”

Post-transcriptional regulation of cytokine and growth factor signaling in cancer

“…Maintaining appropriate balances between RNA-BPs that degrade or stabilize ARE- or GRE-containing mRNAs is a mechanism to ensure appropriate expression of these transcripts and to sustain healthy homeostasis. Understanding the crosstalk between CELF1, ZFP36, ELAVL1 and other RNA-BPs may uncover novel therapeutic strategies to fine-tune the balance in cell growth and cell death pathways involved in human cancer [201, 202]. In the future, more work needs to be done to develop interventions targeting post-transcriptional mechanisms involved in cancer pathogenesis.…”