Abstract
Among the most challenging of clinical targets for cancer immunotherapy are Tumor Associated Carbohydrate Antigens (TACAs). To augment immune responses to TACA we are developing carbohydrate mimetic peptides (CMPs) that are sufficiently potent to activate broad-spectrum anti-tumor reactivity. However, the activation of immune responses against terminal mono- and disaccharide constituents of TACA raises concerns regarding the balance between “tumor destruction” and “tissue damage”, as mono- and disaccharides are also expressed on normal tissue. To support the development of CMPs for clinical trial testing, we demonstrate in preclinical safety assessment studies in mice that vaccination with CMPs can enhance responses to TACAs without mediating tissue damage to normal cells expressing TACA. BALB/c mice were immunized with CMPs that mimic TACAs reactive with Griffonia simplicifolia lectin 1 (GS-I), and tissue reactivity of serum antibodies were compared with the tissue staining profile of GS-I. Tissues from CMP immunized mice were analyzed using hematoxylin and eosin stain, and Luxol-fast blue staining for myelination. Western blots of membranes from murine mammary 4T1 cells, syngeneic with BALB/c mice, were also compared using GS-I, immunized serum antibodies, and naive serum antibodies. CMP immunization enhanced glycan reactivities with no evidence of pathological autoimmunity in any immunized mice demonstrating that tissue damage is not an inevitable consequence of TACA reactive responses.
Highlights
Anti-tumor immune responses are a facet of the tissue-specific autoimmune phenomenon [1], the generation of immune responses to tissue rejection antigens represents an important conceptual approach in cancer immunotherapy
While most studies emphasize the cellular arm of the immune response in tumor rejection, the pathology observed from tumor-reactive antibodies can mirror autoimmune-mediated tissue damage [3], much like that observed for hyperacute rejection of xenotransplanted organs mediated by natural antibodies against the xeno-carbohydrate antigen Galα1-3Galβ1- 4GlcNAc-R (α-Gal) [4]
Carbohydrate residues reactive with Griffonia simplicifolia lectin 1 (GS-I) were previously shown to be present on the surface of highly malignant murine tumors but absent or expressed in much lower amounts on the surface of low malignant cells isolated from the same parent tumors [14]
Summary
Anti-tumor immune responses are a facet of the tissue-specific autoimmune phenomenon [1], the generation of immune responses to tissue rejection antigens represents an important conceptual approach in cancer immunotherapy. The cross-reactivity of GS-I with murine and human cells and tissue can be used to assess pathology in preclinical safety studies of immune responses to CMPs with the potential to cross-react with mono- and disaccharide moieties because the expression of GS-1 reactive antigens are presumed to be ubiquitously expressed in mice. The observation of a low level response to CMPs 106 and 107, albeit enough to mediate tumor growth inhibition, shifts the paradigm in thinking that a robust anti-tumor response is required for an effective therapy These results clearly demonstrate striking context sensitivity in the immune recognition of endothelial cells expressing carbohydrate antigens, a subtlety that must be better understood for inducing immunity to tissue rejection antigens containing. TACA to treat cancer and minimize complications involving immune pathology responses
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