Tumor-induced endothelial cell surface heterogeneity directly affects endothelial cell escape from a cell-mediated immune response in vitro

Abstract

Immune-mediated damage to tumor vessels is a potential means of preventing solid tumor progression. Antiangiogenic cancer vaccines capable of inducing this kind of damage include formulations comprised of endothelial cell-specific antigens. Identification of antigens capable of eliciting efficient vaccination is difficult because the endothelial cell phenotype is affected by surrounding tissues, including angiogenic stimuli received from surrounding tumor cells. Therefore, phenotype endothelial cell variations (heterogeneity) were examined in the context of the development of an efficient vaccine using mass spectrometry-based cell surface profiling. This approach was applied to primary human microvascular endothelial cell (HMEC) cultures proliferated under growth stimuli provided by either normal tissues (growth supplement from human hypothalamus) or cancer cells (MCF-7, LNCap and HepG2). It was found that tumors induced pronounced, tumor type-dependent changes to HMEC surface targets that in an in vitro model of human antiangiogenic vaccination directly facilitated HMEC escape from cytotoxic T cell-mediated cell death. Furthermore, it was found that tumors influenced the HMEC phenotype unidirectionally and that HMEC imunogenicity was reciprocal to the intensity of tumor-induced changes to the HMEC surface. These findings provide data for the design of tumor-specific endothelial cell based vaccines with sufficient immunogenicity without posing a risk to the elicitation of autoimmunity if administered in vivo.

Design of universal cancer vaccines using natural tumor vessel-specific antigens (SANTAVAC)

“…Cancer cells change the HMEC surface antigens through a cancer cell type-independent www.taylorandfrancis.commechanism, suggesting that HMEC heterogeneity is a result of differences in the strength of growth signals. 37 This observation led researchers to hypothesize that the tumor would affect the HMEC surface profile in the same manner in vivo as in vitro, and that tumor-induced changes in the HMEC antigenic profile would be a consequence of the magnitude of the growth stimulus. Distance also influences the tumor's effects on the EC antigenic profile.…”

“…37 Previous studies have suggested that k reflects the intensity of tumor-induced changes at the cell surface, and b reflects the immunogenicity of cell surface targets associated with these changes. Variations in k and b have been demonstrated to be interrelated.…”

“…Variations in k and b have been demonstrated to be interrelated. 37 An additional consideration in vaccine preparation is whether auto-or alloantigens should be used. Although autoantigens elicit high killing rates of the target cells after vaccination, using allogeneic antigens allows the patient's own biomaterial to be excluded from vaccine preparation, thereby simplifying research and development activities and facilitating vaccine implementation in clinical practice.…”

“…1A) in the presence of tumor-conditioned medium collected from different cancer cells. [37][38][39][40] Changes in the cell surface profiles were characterized by cell proteomic footprinting (CPF), an advanced proteomics approach used to characterize cell phenotypes via mass spectrometric analysis of extracellular surface (Fig. 2).…”

Effects of CD40 ligation combined with chemotherapy drugs on human breast cancer cell lines

“…1,2 In many tumour models, CD40-ligand (CD40L)-mediated signals stimulate host anti-tumour immunity [3][4] and significantly increase tumour incidence in Cd40 gene knockout mice. 5 Using CD40 as the target molecule, new biological therapies for cancer have been developed wherein CD40/CD40L signals are stimulated using CD40 antibody, CD40L recombinant products or tumour vaccines with cDNA in order to inhibit tumour growth in epithelial cells.…”