Emerging A New Strategy for the Antitumor Immunotherapy: Pharmacological Modulation of the Ca²⁺/Camp Signaling Interaction

Author(s): Afonso Caricati-Neto, Paolo Ruggero Errante, Francisco Sandro Menezes-Rodrigues and Leandro Bueno Bergantin

Cancer is a major public health problem and the second leading cause of mortality around the world. Antitumor immunotherapy using monoclonal antibodies is considered selective and efficient in the treatment of different types of tumors, but its cost and toxic effects limit its application. Many tumor microenvironments, including lymphoma and carcinoma, are enriched in immune suppressive cells that contribute to immune exhaustion by means expression of inhibitory ligands, suppressive cytokines, and tumor-promoting factors. Antitumor therapies targeted to reduce the induction, recruitment, or suppressive activities of the immune cells have been investigated. New antitumor strategies using drugs targeted to intracellular signaling involved in cell proliferation and survival, angiogenesis, and metastasis have become promising in recent years. Thus, our discovery of the role of functional interaction between intracellular signaling pathways mediated by calcium ions (Ca2+) and cyclic adenosine monophosphate (cAMP) (Ca2+/cAMP signaling interaction) in these cellular responses, opened a great avenue for the development of new antitumor therapeutic strategies. Here, we discuss how the combined use of monoclonal antibodies with drugs that modulate the Ca2+/cAMP signaling interaction to reduce tumor growth could be a potential strategy in the antitumor immunotherapy due to the increment of antitumor efficacy and reduction of adverse effects.