Inflammation-Induced Abnormal Expression of Self-molecules on Epithelial Cells: Targets for Tumor Immunoprevention

Abstract

Tumor-associated antigens (TAAs) are self-molecules abnormally expressed on tumor cells, which elicit humoral and cellular immunity and are targets of immunosurveillance. Immunity to TAAs is found in some healthy individuals with no history of cancer and correlates positively with a history of acute inflammatory and infectious events and cancer risk reduction. This suggests a potential role in cancer immunosurveillance for the immune memory elicited against disease-associated antigens (DAAs) expressed on infected and inflammed tissues that are later recognized on tumors as TAAs. To understand probable sources for DAA generation, we investigated in vitro the role of inflammation that accompanies both infection and carcinogenesis. After exposure of normal primary breast epithelial cells to pro-inflammatory cytokines IL1β, IL6, and TNFα, or macrophages producing these cytokines, we saw transient overexpression of well-known TAAs, carcinoembryonic antigen (CEA) and Her-2/neu, and overexpression and hypoglycosylation of MUC1. We documented inflammation-induced changes in the global cellular proteome by 2D Difference Gel Electrophoresis (2D-DIGE) combined with mass spectrometry and identified seven new DAAs. Through gene profiling, we showed that the cytokine treatment activated NF-κB and transcription of the identified DAAs. We tested three in vitro-identified DAAs, Serpin B1, S100A9, and SOD2, and found them overexpressed in premalignant and malignant breast tissues as well as in inflammatory conditions of the colon, stomach, and liver. This new category of TAAs, which are also DAAs, represent a potentially large number of predictable, shared, immunogenic, and safe antigens to use in preventative cancer vaccines and as targets for cancer therapies.

A novel rat model of vertebral inflammation–induced intervertebral disc degeneration mediated by activating cGAS/STING molecular pathway

“…The presence of the latter is strongly determined by LPS, 32 which also induces in macrophages the release of several inflammatory cytokines, including IL‐1β, IL‐6 and TNF‐α. 43 In VI‐IVDD, M1 macrophages infiltrated massively, and inflammatory cytokines were abundantly produced. In the Mid group, inflammatory signs are present in the adjacent IVDs, in both sides of the vertebral body, whereas in the NIVD group, inflammation was mainly concentrated in the adjacent IVD in the proximity of the trigger point of inflammation.…”

LCVM infection generates tumor antigen-specific immunity and inhibits growth of nonviral tumors

“…The data presented here add an immune mechanism to other postulated mechanisms of natural protection against cancer and the positive role of history of acute infections in reducing lifetime cancer risk. 13 , 19 , 29–32 We show that this protective effect is likely mediated through the generation of immune responses and memory to transiently aberrantly expressed self-molecules that are shared by infected cells and cancer cells. We used here a model infection of mice with two strains of the same virus, LCMV-Arm that causes acute infections and LCMV-Cl-13 that establishes a chronic infection.…”

Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma

“…Sex differences in response to vaccination and various immunotherapies have been previously observed and explanations proposed (44)(45)(46)(47). MUC1 vaccine may be more immunogenic in females than in males because females experience a larger number of epithelial inflammatory events such as ovulatory cycles, endometriosis, and use of intrauterine devices, that affect epithelial tissues and transiently change MUC1 expression from normal to the tumor-like form , which can lead to spontaneous, albeit low level, immune priming and immune memory for abnormal MUC1 (48,49). This immune memory could facilitate the response to the MUC1 vaccine resulting in a stronger immune response.…”