Tumor endothelial marker 1–specific DNA vaccination targets tumor vasculature

Facciponte, John G.; Ugel, Stefano; Sanctis, Francesco De; Li, Chunsheng; Wang, Liping; Nair, Gautham; Sehgal, Sandy; Raj, Arjun; Matthaiou, Efthymia Iliana; Coukos, George; Facciabene, Andrea

doi:10.1172/jci67382

Cited by 65 publications

(84 citation statements)

References 84 publications

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“…The normalized TME is conducive to DC maturation and the subsequent cross-priming of "second set" CD8 C T cell responses reactive against TAA acquired by DC within the TME. 10,51 This effectively drives a broadening in the antitumor T cell repertoire based on an "epitope spreading" paradigm, 51,52 such as we observed in the case of DLK1/DLK2-based therapeutic vaccines leading to the development of anti-gp100 CD8 C T cell responses in the B16 melanoma model (Fig. S2).…”

Section: Discussionmentioning

confidence: 88%

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

et al. 2017

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When compared with vascular cells in normal tissues, pericytes and vascular endothelial cells (VEC) in tumor blood vessels exhibit altered morphology and epigenetic programming that leads to the expression of unique antigens that allow for differential recognition by CD8 C T cells. We have previously shown that the Notch antagonist delta-like homolog 1 (DLK1) is a tumor pericyte-associated antigen expressed in setting of melanoma and a range of carcinomas. In this report, we show that therapeutic vaccination against DLK1 in murine models results in slowed tumor growth, but also to the compensatory expression of the DLK1 homolog, DLK2, by tumor-associated pericytes. Vaccines targeting both DLK1 and DLK2 resulted in superior antitumor benefits in association with improved activation and recruitment of antigen-specific Type 1 CD8 C T cells, reduced presence of myeloid-derived suppressive cells, T regulatory cell and tumor vascular normalization. The antitumor efficacy of vaccines coordinately targeting DLK1 and DLK2 was further improved by inclusion of PD-L1 blockade, thus defining a combination immunotherapy theoretically suitable for the treatment of a broad range of solid (vascularized) cancers.

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Section: Discussionmentioning

confidence: 88%

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

et al. 2017

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“…Vaccine therapy using targeted molecules, such as tumor endothelial marker 1, TEM8, fibroblast growth factor receptor or VEGFR2, which are overexpressed on TECs, has been studied by many investigators. [31][32][33][34] However, a TEC-specific vaccine therapy with few side-effects has not been developed as yet since such molecules are also expressed on the cell surface of normal blood vessel endothelial cells. In this regard, our results strongly suggest that tumor vaccine therapy only targets tumor, but not physiological, angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Cancer Vaccine Therapy Using Tumor Endothelial Cells as Antigens Suppresses Solid Tumor Growth and Metastasis

Nomura

Hirata

Shimaoka

et al. 2017

Biological & Pharmaceutical Bulletin

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Tumor angiogenesis plays an important role in tumor growth and metastasis, with tumor cells requiring nutrients and oxygen via blood flow for their proliferation. In comparison, angiogenesis also occurs under normal physiological conditions, such as wound healing and in the formation of the corpus luteum. Herein, we report on the development of a novel dendritic cell (DC) vaccine therapy using tumor endothelial cells (TECs) derived from tumor vessels as tumor antigens. After density gradient centrifugation and the detection of angiotensin-converting enzyme activities, a TEC-rich fraction was separated from solid tumor tissues. Prophylactic or therapeutic immunization using DCs pulsed with TECs as vaccine antigens significantly suppressed solid tumor growth in a Colon-26 colorectal adenocarcinoma tumor-bearing mouse model, compared with the use of tumor cells as DC vaccine antigens. Tumor tissues showed reduced angiogenesis. However, vaccination using DCs pulsed with TECs did not inhibit physiological angiogenesis as evidenced by a wound healing assay. Additionally, in a B16/BL6 mouse melanoma lung metastasis model, DC vaccination using TECs derived not only from the same tumor tissue but from a different type of tumor also suppressed metastasis. These results thus show that cancer vaccine therapy targeting TECs is an effective therapy against angiogenesis in several types of cancer, but does not affect normal blood vessel growth.Key words tumor endothelial cell; angiogenesis; dendritic cell; vaccine; metastasis Endothelial cells that enable tumor angiogenesis are recruited from neighboring, pre-existing capillaries 1,2) by tumor angiogenesis mediators, such as vascular endothelial growth factor (VEGF),3) fibroblast growth factors, 4) and transforming growth factor, 5) in the process of tumor progression or metastasis.6,7) Newly produced blood vessels, which are constructed by tumor endothelial cells (TECs), provide oxygen and nutrients, and remove metabolic waste from tumor cells; tumor cell proliferation also depends on new blood vessel formation. 6,8) In addition, TECs in different types of cancers express common, tumor-associated antigens (TAAs), since the tumor's new blood vessels are constructed from endothelial cells of the host. In this regard, it is expected that the inhibition of angiogenesis in tumor tissue will effectively induce tumor regression for several types of cancer, compared with the direct inhibition of tumor cells themselves. In fact, several antiangiogenic agents, such as the VEGF receptor and tyrosine kinase inhibitor, sunitinib, 9) and the anti-VEGF antibody, bevacizumab, 10) are commonly applied in clinical practice today since they tend to show a survival advantage for patients. However, angiogenesis also occurs during the processes of wound healing and corpus luteum formation, 11) with the implication that the clinical application of antiangiogenic agents in cancer patients may result in damage to normal blood vessels, 12) in addition to those of the tumor. Therefore, the selective in...

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“…Tumors were embedded in OCT and immediately snap-frozen in dry ice. Sections (6 mm thick) were stained for CD3, as previously described (24). Slides were analyzed in a blinded fashion by two independent observers.…”

Section: Cd3mentioning

confidence: 99%

“…After incubation, plates were washed with PBS and Tween 20, ELISPOT was performed, and spots were counted using an automated ELISPOT reader (Autoimmun Diagnostika) (24).…”

Section: Isolated Cd3mentioning

confidence: 99%

“…To determine whether the antitumor response by mitochondriaenriched RENCA vaccine is cellular or humoral in nature, we performed adoptive transfer of total CD3 + T cells, CD4 + T cells, CD8 + T cells, or serum from mitochondria-enriched immunized + cells from nonimmunized mice were included as additional controls (24). Fig.…”

Section: Renca Mitochondria Vaccine Drives a T Cell-specific Immune Rmentioning

confidence: 99%

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A Tumor Mitochondria Vaccine Protects against Experimental Renal Cell Carcinoma

Pierini

Fang

Rafail

et al. 2015

The Journal of Immunology

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Mitochondria provide energy for cells via oxidative phosphorylation. Reactive oxygen species, a byproduct of this mitochondrial respiration, can damage mitochondrial DNA (mtDNA), and somatic mtDNA mutations have been found in all colorectal, ovarian, breast, urinary bladder, kidney, lung, and pancreatic tumors studied. The resulting altered mitochondrial proteins or tumor-associated mitochondrial Ags (TAMAs) are potentially immunogenic, suggesting that they may be targetable Ags for cancer immunotherapy. In this article, we show that the RENCA tumor cell line harbors TAMAs that can drive an antitumor immune response. We generated a cellular tumor vaccine by pulsing dendritic cells with enriched mitochondrial proteins from RENCA cells. Our dendritic cell–based RENCA mitochondrial lysate vaccine elicited a cytotoxic T cell response in vivo and conferred durable protection against challenge with RENCA cells when used in a prophylactic or therapeutic setting. By sequencing mtDNA from RENCA cells, we identified two mutated molecules: COX1 and ND5. Peptide vaccines generated from mitochondrial-encoded COX1 but not from ND5 had therapeutic properties similar to RENCA mitochondrial protein preparation. Thus, TAMAs can elicit effective antitumor immune responses, potentially providing a new immunotherapeutic strategy to treat cancer.

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Tumor endothelial marker 1–specific DNA vaccination targets tumor vasculature

Cited by 65 publications

References 84 publications

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

Cancer Vaccine Therapy Using Tumor Endothelial Cells as Antigens Suppresses Solid Tumor Growth and Metastasis

A Tumor Mitochondria Vaccine Protects against Experimental Renal Cell Carcinoma

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