# Oxidatively Modified Proteins: Cause and Control of Diseases
## 5 Therapeutic Use of oxPTMs  
Although the cellular mechanism and immune cell interactions are partly incompletely understood, increased immunogenicity of oxPTMs has been shown already in model systems of inflammation [97], diabetes [67], and allergy [98]. In such a way, not only PTMs, but also protein stability, adjuvants, or other companion substances (e.g., carrier proteins, nanoparticles) can increase the success of immunomodulatory therapeutics. There is a correlation between protein stability and immunogenicity [99], and PTMs can alter protein structure [14; 100]. Thus, PTMs can also act as an adjuvant to improve protective immune response, as was shown for therapeutic vaccination for cancer therapy. Oxidatively modified tumor lysate reduced tumor growth and was more effective than injection with native tumor lysate [93; 101; 102; 103]. This ultimately led to an increase of the anti-tumor T cell receptor repertoire and more durable and clinically apparent anti-tumor effects [94] (Figure 3A). Although tumor lysates consist of a pool of proteins that may mask the immunogenicity of individual proteins, vaccination with tumor-associated proteins alone has so far only generated little success [104; 105]. Instead, typical tumor vaccines consist of either peptides, DNA, or mRNA, or are viral/bacterial-based with different advantages and disadvantages [106; 107; 108; 109]. Non-enzymatic, oxidative PTM proteins or peptides have not come into focus, despite their expected relevance, as observed in inflammatory disease. By contrast, therapeutic vaccination in AD patients with the modified tau peptide or tau peptide in combination with adjuvants has led to vaccine-induced antibodies potentially targeting tau proteins [89; 111; 112]. It appears feasible to use such an approach in oncology also.  
Figure 3: Modified proteins as therapeutics. Vaccination with oxPTM proteins alters antigen-specific T cell activation. (**A**) Cancer cells evade immune response due to the expression of “self” antigens, and the oxPTM vaccine enlarges the T cell repertoire to enable T cell activation. (**B**) In oxPTM-induced diseases, vaccination with modified proteins can dampen by increasing the threshold that is needed for activation.  
In allergy, the goal is not to amplify but to dampen antigen-specific immune responses. Antigen-specific immune cell tolerance is achieved via antigen-specific regulatory T cells (Tregs) [113; 114] that, hence, are one target of tolerogenic vaccines for treating autoimmune diseases (e.g., diabetes type 1, multiple sclerosis) [91; 115; 116] (Figure 3B). Enzymatic or non-enzymatic PTMs may accelerate vaccination success since such vaccines might be able to address the T cells specific for PTM-carrying proteins that are not being targeted when using non-modified proteins or peptides. For example, immunotherapy with modified peanut extract reduced allergenicity in peanut-allergic mice [86; 87]. Studies with modified allergens in patients are challenging and have not yet been completed [117; 118]. Assuming that the modified-allergen vaccine reduces allergenicity, further research should be done to identify the mechanistic basis of immunogenic vs. tolerogenic non-enzymatic protein modifications.