Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–α

  title={Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein–$\alpha$},
  author={Matthew Kraman and Paul J. Bambrough and James N Arnold and Edward W. Roberts and Lukasz Magiera and James O. Jones and Aarthi Gopinathan and David A. Tuveson and Douglas T. Fearon},
  pages={827 - 830}
The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. [] Key Result Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor-α.

Disruption of Anti-tumor T Cell Responses by Cancer-Associated Fibroblasts

Recent advances in the understanding the tumor micro-environment reveals potential new ways for attacking tumor cells, especially T cells.

A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts

It is indicated that the FAP-modified whole-cell tumor vaccine induced strong antitumor immunity against both tumor cells and CAFs and reversed the immunosuppressive effects of tumors by decreasing the recruitment of immunOSuppressive cells and enhancing the recruitmentof effector T cells.

Immunotherapy of tumor with vaccine based on basic fibroblast growth factor-activated fibroblasts

PurposeCancer-associated fibroblasts play a key role in tumor progression. It is conceivable that the breaking of immune tolerance of “self-antigens” associated with tumor cells and tumor stromal is

Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment

MSCs in the tumor environment reduce the efficacy of immunotherapy by creating a functional and anatomic barrier that impairs inflammation, T cell priming and expansion, and T cell function—including recruitment of effector cells.

Antitumor immunity targeting fibroblast activation protein-α in a mouse Lewis lung carcinoma model

The results of the present study suggested that FAP-α, which is preferentially expressed in CAFs, may be considered as a potential target for killing or destroying CAFs within the tumor stromal microenvironment, and may be exploited to develop immunogenic tumor vaccines.

Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment

It is shown that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector resulted in T cell-dependent long-term control of melanomas and reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment.

Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model

A DNA vaccine targeting human FAPα may be an attractive and effective cancer immunotherapy strategy and reduce 4T1 tumor growth through producing FAP α-specific cytotoxic T lymphocyte responses which could kill CAFs.

The Carcinoma-Associated Fibroblast Expressing Fibroblast Activation Protein and Escape from Immune Surveillance

  • D. Fearon
  • Biology, Medicine
    Cancer Immunology Research
  • 2014
The conditional depletion of the FAP+ CAF permits immune control not only of an artificial, transplanted tumor, but also of an autochthonous model of pancreatic ductal adenocarcinoma that replicates the molecular, histologic, clinical, and immunologic characteristics of the human disease.

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

Results implicated that immunization with FAP+ stromal cells led to the disruption of the tumor microenvironment and may provide a novel strategy for immunotherapy of a broad range of cancer.



T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor

The results leave little doubt that the presence of suppressor T cells in T-cell-intact, tumor-bearing mice is responsible for the loss of an earlier generated state of concomitant immunity, and for the inability of intravenously infused, sensitized T cells to cause tumor regression.

IFN-gamma- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers.

It is shown that IFN-gamma and TNF produced by CTLs were crucial for the elimination of established mouse tumors, including ALVs, and bystander killing of ALVs may result from IFN/TNF acting on tumor stroma.

Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors

This study illustrates that the suppression of antitumor immunity by regulatory T cells occurs predominantly at the tumor site, and that local reversal of suppression, even at a late stage of tumor development, can be an effective treatment for well-established cancers.

Tumor Progression Despite Efficient Tumor Antigen Cross-Presentation and Effective “Arming” of Tumor Antigen-Specific CTL1

Data show that tumor-draining APC are not dysfunctional with regard to two crucial processes, in vivo tumor Ag cross-presentation and specific CTL arming, and that failure to prevent tumor growth is not in the induction phase, but in the effector phase and occurs within the tumor itself before the tumor matrix is established.

Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice.

Results indicate that FAP depletion inhibits tumor cell proliferation indirectly, increases accumulation of collagen, decreases myofibroblast content, and decreases blood vessel density in tumors, providing proof of principle that targeting stromal cell-mediated modifications of the tumor microenvironment may be an effective approach to treating epithelial-derived solid tumors.

Tumor‐induced tolerance and immune suppression by myeloid derived suppressor cells

Based on observations of MDSCs, a time‐structured and topologically consistent idea of tumor‐dependent tolerance progression in tumor‐bearing hosts is presented.

Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer

Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, it is found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA.

Tumor Progression Can Occur despite the Induction of Very High Levels of Self/Tumor Antigen-Specific CD8+ T Cells in Patients with Melanoma

The mere presence of profoundly expanded numbers of vaccine-induced, self/tumor Ag-specific T cells cannot by themselves be used as a “surrogate marker” for vaccine efficacy, and the induction of even high levels of antitumor T cells may be insufficient to alter tumor progression.

Inhibition of tumor growth by elimination of granulocytes

An antigen retention variant is analyzed and it is found that the variant tumor cells grow at the same rate as the parental tumor cells in vitro, but grew more rapidly than the parental cells in the T cell-deficient host.