Targeting innate immune pathways in cancer immunotherapy: state of the art

Complement-based cancer immunotherapy is gaining momentum in recent years due to the growing number of therapeutic anti-tumor antibodies that are receiving approval for clinical trials and are currently used in clinical cancer care. Even though some anti-tumor antibodies have shown moderate therapeutic efficacy, most of them still lag behind, having failed to produce adequately effective responses. The urging need for a therapeutic platform that will enhance both the humoral and cellular effects of antibody treatment prompts the design of more effective combinatorial therapeutics for enhancing complement-mediated tumor cytotoxicity in cancer patients. Cancer cells express or "sequester" host membrane-bound and fluid-phase complement regulators in order to evade complement attack and establish an immunosuppressive microenvironment for tumor growth. Moreover, membrane complement regulators appear to modulate several aspects of T-cell immunity that are relevant to the anti-tumor, adaptive T-cell response. Recently, the concept that complement activation is unfavorable for tumor growth has been drastically challenged by evidence that points to a novel immunomodulatory role of complement in the tumor microenvironment. Taken together, these findings form a new conceptual framework that integrates innate immunity to cancer development. Furthermore, they are anticipated to lead to the rational design of strategies that will exploit innate immune systems, such as complement, in a patient-oriented, "individualized" manner for effective cancer immunotherapy.