Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors

Zhang, Ying; Ertl, Hildegund C. J.

doi:10.18632/oncotarget.7818

Cited by 83 publications

(79 citation statements)

References 56 publications

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“…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].…”

Section: Drugs That Can Influence Msc-mediated Immune Regulationmentioning

confidence: 99%

“…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].…”

Section: Msc As Target Cells For Anti-tumor Vaccinesmentioning

confidence: 99%

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

Poggi

Giuliani

2016

Vaccines

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The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC) activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT), a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity.

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Section: Drugs That Can Influence Msc-mediated Immune Regulationmentioning

confidence: 99%

Section: Msc As Target Cells For Anti-tumor Vaccinesmentioning

confidence: 99%

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

Poggi

Giuliani

2016

Vaccines

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“…When FAP expressed in stromal cells was targeted with CAR T cells in a preclinical cancer model, tumor cell growth was inhibited (215). Similarly, when stromal cells that express FAP in a murine model were eliminated, tumor infiltrating CD8 + T cell activity and longer survival of mice harboring tumors were enhanced (216). Thus, adapting the tumor microenvironment to favor tumor eradication is fraught with obstacles but presents an encouraging approach.…”

Section: Challengesmentioning

confidence: 99%

“…These have the advantage that they can be expanded into large batches and used as “off the shelf” therapeutic allogeneic CAR T cells with broad applicability (216). The TCR has been disrupted by TALEN-mediated site-specific mutagenesis to eliminate the risk of graft versus host disease.…”

Section: Challengesmentioning

confidence: 99%

Cancer Immunotherapy: Whence and Whither

Stambrook

Maher

Farzaneh

2017

Molecular Cancer Research

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The current concepts and practice of cancer immunotherapy evolved from classical experiments that distinguished "self" from "non-self" and the finding that humoral immunity is complemented by cellular immunity. Elucidation of the biology underlying immune checkpoints and interactions between ligands and ligand receptors that govern the immune system's ability to recognize tumor cells as foreign has led to the emergence of new strategies that mobilize the immune system to reverse this apparent tolerance. Some of these approaches have led to new therapies such as the use of monoclonal antibodies (mAbs) to interfere with the immune checkpoint. Others have exploited molecular technologies to re-engineer a subset of T cells to directly engage and kill tumor cells, particularly those of B cell malignancies. However, before immunotherapy can become a more effective method of cancer care, there are many challenges that remain to be addressed and hurdles to overcome. Included are manipulation of tumor microenvironment (TME) to enhance T effector cell infiltration and access to the tumor, augmentation of tumor MHC expression for adequate presentation of tumor associated antigens, regulation of cytokines and their potential adverse effects, and reduced risk of secondary malignancies as a consequence of mutations generated by the various forms of genetic engineering of immune cells. Despite these challenges, the future of immunotherapy as a standard anti-cancer therapy is encouraging.

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“…In leukemic or lymphoma models of disease, adoptive transfer of genetically modified T cells come into contact with the tumor cells almost immediately, reducing the need to localize and persist at the tumor site. In contrast, solid tumors present numerous challenges; with issues arising involving the persistence and survival of transferred T cells, the inability of T cells to penetrate the tumor mass and maintaining their effector cell function within an immunosuppressive tumor microenvironment [8–10]. The ability of CAR T cells to overcome these multiple factors alone has proven to be inadequate.…”

Section: Introductionmentioning

confidence: 99%

A role for multiple chimeric antigen receptor-expressing leukocytes in antigen-specific responses to cancer

et al. 2016

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While adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells can induce remission of some tumors, the role of other CAR-modified leukocytes is not well characterized. In this study, we characterize the function of leukocytes including natural killer (NK) cells, macrophages and CAR T cells from transgenic mice expressing a CAR under the control of the pan-hematopoietic promoter, vav, and determine the ability of these mice to respond to ERB expressing tumors. We demonstrate the anti-tumor functions of leukocytes, including antigen specific cytotoxicity and cytokine secretion. The adoptive transfer of CAR T cells provided a greater survival advantage in the E0771ERB tumor model than their wildtype (WT) counterparts. In addition, CAR NK cells and CAR T cells also mediated increased survival in the RMAERB tumor model. When challenged with Her2 expressing tumors, F38 mice were shown to mount an effective immune response, resulting in tumor rejection and long-term survival. This was shown to be predominantly dependent on both CD8+ T cells and NK cells. However, macrophages and CD4+ T cells were also shown to contribute to this response. Overall, this study highlights the use of the vav-CAR mouse model as a unique tool to determine the anti-tumor function of various immune subsets, either alone or when acting alongside CAR T cells in adoptive immunotherapy.

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Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors

Cited by 83 publications

References 56 publications

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

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

Cancer Immunotherapy: Whence and Whither

A role for multiple chimeric antigen receptor-expressing leukocytes in antigen-specific responses to cancer

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