Author's reply to: Could cross‐immunological reactivity to Trypanosoma cruzi antigens be considered a rational strategy for designing vaccines against cancer?

Dear Editor, We wish to thank Dr. Dias Novaes and colleagues for their comments on our recently published article concerning the anti-tumor potential of Trypanosoma cruzi antigens. One of the major challenges in the development of an efficient anticancer vaccine is to overcome immune tolerance developed by tumors. Vaccination with tumor-associated antigens (TAA) coming from evolutionary distant organisms (such as parasites) should be useful to override tolerance problems encountered with human TAA-based cancer therapeutic approaches. In our study, using two rat models which reproduce human carcinogenesis, we demonstrated that vaccination with T. cruzi antigens significantly reduces colon and mammary cancer development, via induction of both innate and adaptive immune responses. As discussed in this original article, the cross-reactivity between T. cruzi and cancer tissues could be explained, at least in part, by molecular mimicry, an important mechanism leading to autoimmunity in Chagas disease. The molecular mechanisms that lead to autoimmunity in patients with Chagas disease could help to understand some aspects of the anti-tumor immune-induced response elicited by T. cruzi molecules. Nonetheless, much work is still needed to allow the identification of T. cruzi stimulatory components or antigens involved in the cross-reaction between this parasite and cancer cells to support this hypothesis. Although immunotherapy holds great promise for the treatment of cancer, it is clear that many immunological treatments can lead to immune reactions against normal tissues. Treatment-related toxicity has correlated with better responses in some cases. For example, vitiligo may occur after administration of melanoma vaccines and is associated with a beneficial outcome. Doubtless, a better understanding of the different mechanisms involved in immune-mediated damage of normal tissues will enable the development of more potent and specific strategies of immunotherapy for treating cancer. In this context, it is interesting to highlight that the conditions and route of administration of a T. cruzi immunogen might impact in the degree of induced autoimmunity. Indeed, immunization of mice with the T. cruzi cysteine protease cruzipain induced autoantibodies that pathologically inhibit the function of cardiac muscarinic acetylcholine receptors, whereas a DNA vaccine containing the cruzipain gene was found to provide protective immunity against T. cruzi infection without causing cardiac abnormalities. It is becoming increasingly clear that a useful strategy for cancer immunotherapy is a balance between antitumor immunity and immune toxicity. Considering that some T. cruzi molecules induce immunological anti-tumor activity and may be thus exploited to develop a new type of therapeutic vaccine against cancer, it is now important to molecularly identify the parasite components involved in the suppression of tumor growth. Future studies with this individual parasite-derived molecules will enable the functional discrimination of their antitumor capacity from their autoimmunity properties and pave the way for the development of biologically and clinically safer as well as more efficient anticancer immunotherapies.