Abstract
Low antigen expression and an absence of coimmunostimulatory signals may be partly responsible for the low immunogenicity of many tumors. It may be possible to overcome this situation by defining a combination of adjuvants and antigens that can activate a high-avidity antitumor response. Using the poorly immunogenic B16-OVA melanoma cells as tumor model, we tested different combinations of adjuvants and antigens to treat established tumors. In the absence of exogenous antigens, repeated administration of the TLR7 ligand Imiquimod together with anti-CD40 agonistic antibodies activated only innate immunity, which was insufficient to reject intradermal tumors. Administering this adjuvant combination together with OVA as a tumor antigen induced T-cell responses that delayed tumor growth. However, administering a combination of anti-CD40 plus TLR3 and TLR7 ligands, together with antigen targeting to dendritic cells through TLR4, was sufficient to induce tumor rejection in 50% of mice. This response was associated with a greater activation of innate immunity and induction of high-avidity polyfunctional CD8(+) T-cell responses, which each contributed to tumor rejection. This therapy activated T-cell responses not only against OVA, which conferred protection against a rechallenge with B16-OVA cells, but also activated T-cell responses against other melanoma-associated antigens. Our findings support the concept that multiple adjuvant combination and antigen targeting may be a useful immunotherapeutic strategy against poorly immunogenic tumors.
Highlights
Tumor immunotherapy is aimed at inducing immune responses to destroy tumor cells [1]
Unlike danger signals associated with pathogens, such as toll-like receptor (TLR) ligands, or inflammatory signals, which induce dendritic cells (DC) maturation, tumor cells do not release immunogenic danger signals, unless they are submitted to radio- or chemotherapy [3]
When this protocol was applied to the B16-OVA melanoma model, no differences in tumor growth and survival were observed between control and vaccinated mice (Supplementary Fig. S1A and B), demonstrating the poor immunogenicity and recognition of B16-OVA cells
Summary
Tumor immunotherapy is aimed at inducing immune responses to destroy tumor cells [1]. To overcome the low tumor immunogenicity, new therapeutic strategies are based on the use of adjuvants (molecules able to induce DC maturation) with or without exogenously added tumor antigens, which will activate DC to properly present tumor antigens to T cells and trigger their effector functions [5]. With this aim, a great effort has been made to characterize DC-activating ligands to be used as adjuvant molecules, due to their immunostimulatory and/or targeting properties, and avoid the use of microorganisms containing undefined adjuvant mixtures [6]. Development of therapeutic strategies based on the use of molecularly defined components is a main goal in tumor immunology
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