Abstract
Immunotherapy has become an important ally in the fight against distinct types of cancer. However, the metabolic plasticity of the tumor environment frequently influences the efficacy of therapeutic procedures, including those based on immunological tools. In this scenario, immunometabolic adjuvants arise as an alternative toward the development of more efficient cancer therapies. Here we demonstrated that the combination of melatonin, a neuroimmunomodulator molecule, and an indoleamine 2,3-dioxygenase (IDO) inhibitor (1-methyl-DL-tryptophan, DL-1MT) improves the efficacy of an immunotherapy (gDE7) targeting human papillomavirus (HPV)-associated tumors. Melatonin or IDO inhibitors (D-1MT and DL-1MT) directly reduced proliferation, migration, adhesion and viability of a tumor cell line (TC-1), capable to express the HPV-16 E6 and E7 oncoproteins, but could not confer in vivo antitumor protection effects. Nonetheless, combination of gDE7 with melatonin or D-1MT or DL-1MT enhanced the antitumor protective immunity of gDE7-based vaccine in mice. Notably, expression of IDO1 in stromal cells and/or immune cells, but not in tumor cells, inhibited the antitumor effects of the gDE7, as demonstrated in IDO1-deficient mice. Finally, co-administration of gDE7, melatonin and DL-1MT further improved the protective antitumor effects and the numbers of circulating E7-specific CD8+ T cells in mice previously transplanted with TC-1 cells. The unprecedented combination of melatonin and IDO inhibitors, as immunometabolic adjuvants, thus, represents a new and promising alternative for improving the efficacy of immunotherapeutic treatments of HPV-associated tumors.
Highlights
Human papillomaviruses (HPV) are widely spread pathogens responsible for one of the most common sexually transmitted diseases worldwide [1]
We evaluated the therapeutic potential of a novel immunotherapy focusing on three components: melatonin, 1MT and an human papillomavirus (HPV)-16 therapeutic vaccine based on a recombinant protein generated after the genetic fusion of the HPV-16 E7-oncoprotein with the envelope glycoprotein of herpes virus simplex virus (HSV)
Considering the increase association of IDO1 expression and HPV-induced malignancies, incorporation of two immunometabolic adjuvants, melatonin and IDO1 inhibitors, to an anti-cancer vaccine resulted in enhanced in vivo antitumor effectiveness without visually noticeable side effects usually observed with other anti-cancer treatments
Summary
Human papillomaviruses (HPV) are widely spread pathogens responsible for one of the most common sexually transmitted diseases worldwide [1]. All cervical cancers and around 90% of squamous anal cancers can be attributable to HPV infection [2]. The correlation between HPV infection and other anogenital and oropharyngeal cancers is steadily growing [3]. The classification into low-risk or high-risk HPV genotypes relies on the oncogenic potential during persistent infection in the cervical tissue [2]. In this scenario, the constitutive expression of E6 and E7 oncoproteins, leading to cellular transformation and immortalization, is mandatory for the onset and maintenance of HPV-associated cancers by high-risk genotypes [4]. HPV-16 infection is more prevalent than any other high-risk HPV genotype in most regions worldwide [5]
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