A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice

Abstract

Fibroblast activation protein (FAP) is highly expressed in the tumor-associated fibroblasts (TAFs) of most human epithelial cancers. FAP plays a critical role in tumorigenesis and cancer progression, which makes it a promising target for novel anticancer therapy. However, mere abrogation of FAP enzymatic activity by small molecules is not very effective in inhibiting tumor growth. In this study, we have evaluated a novel immune-based approach to specifically deplete FAP-expressing TAFs in a mouse 4T1 metastatic breast cancer model. Depletion of FAP-positive stromal cells by FAP-targeting immunotoxin αFAP-PE38 altered levels of various growth factors, cytokines, chemokines and matrix metalloproteinases, decreased the recruitment of tumor infiltrating immune cells in the tumor microenvironment and suppressed tumor growth. In addition, combined treatment with αFAP-PE38 and paclitaxel potently inhibited tumor growth in vivo. Our findings highlight the potential use of immunotoxin αFAP-PE38 to deplete FAP-expressing TAFs and thus provide a rationale for the use of this immunotoxin in cancer therapy.

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].…”

A multi-antigen vaccine in combination with an immunotoxin targeting tumor-associated fibroblast for treating murine melanoma

“… 26 , 30 We have recently found that αFAP-PE38 treatment altered levels of various growth factors, cytokines, chemokines, and matrix metalloproteinases in the tumor microenvironment. 27 Based on the existing CD45 − FAP + stromal population in the B16 melanoma model, as shown in Figure 3b , we hypothesized that αFAP-PE38 treatment might have an additive, or synergistic, effect on the antitumor activity of LV-3Ag immunization. Therefore, the efficacy of LV-3Ag immunization combined with αFAP-PE38 (hereinafter termed “combination treatment”) treatment was evaluated.…”

“…It has been recently reported that VEGF produced in the tumor microenvironment enhanced the expression of PD-1 and other inhibitory checkpoints involved in CD8 + T-cell exhaustion. 48 We have previously shown that immunotoxin αFAP-PE38 reduced the level of VEGF in the tumor microenvironment, 27 suggesting that the observed reduction of PD-1 in CD8 + T cells could be partially due to the variation of VEGF. Thus, our current study not only provided proof-of-principle for the use of multiple tumor antigens toward the improvement of antitumor efficacy, but also highlighted the potential of targeting TAFs to improve current immunotherapeutic approaches against cancer.…”

“… 26 In our previous study, we have shown that depletion of FAP-expressing stromal cells reduced the recruitment of infiltrating tumor-associated macrophages, attenuated angiogenesis to deprive tumor cells of required nutrients and oxygen, and inhibited tumor cell growth. 27 In addition, we and others 25 have shown that depletion of FAP-positive stromal cells can also modulate the expression profile of growth factors, cytokines, and chemokines, thus altering the tumor microenvironment.…”