Phytochemicals as Immunomodulatory Agents in Melanoma

Abstract

Cutaneous melanoma is an immunogenic highly heterogenic tumor characterized by poor outcomes when it is diagnosed late. Therefore, immunotherapy in combination with other anti-proliferative approaches is among the most effective weapons to control its growth and metastatic dissemination. Recently, a large amount of published reports indicate the interest of researchers and clinicians about plant secondary metabolites as potentially useful therapeutic tools due to their lower presence of side effects coupled with their high potency and efficacy. Published evidence was reported in most cases through in vitro studies but also, with a growing body of evidence, through in vivo investigations. Our aim was, therefore, to review the published studies focused on the most interesting phytochemicals whose immunomodulatory activities and/or mechanisms of actions were demonstrated and applied to melanoma models.

Keywords: cytokynes; immunomodulation; inflammation; melanoma; phytochemicals; plant secondary metabolites.

Figure 1

Number of publications indexed on PubMed is reported on four groups: those published between 1951–1970, 1971–1990, 1991–2010 or from 2011 up today (2011–2022: please note that the last one refers to only 11 years), filtered by containing within title/text the name of a category of natural compounds. In upper panel the second search criterion was “melanoma” while in the lower panel the second criterion was “immunomodul*”.

Figure 2

Melanoma cells modulate the communications with cells of the tumor microenvironment through the release of soluble factors in order to promote tumor dissemination, angiogenesis and the establishment of an immune suppressive niche. Cytotoxic T lymphocyte (CTL), dendritic cell (DC), natural killer cell (NK), tumor-associated macrophage (TAM), myeloid-derived suppressor cell (MDSC), T regulatory cell (Treg), cancer-associated fibroblast (CAF), interleukin 8 (IL-8), 1β (IL- 1β), 6 (IL-6), 10 (IL-10), prostaglandin E2 (PGE2), C-X-C motif chemokine 12 (CXCL12), vascular endothelial growth factor (VEGF), tumor growth factor β (TGF- β), metalloproteinases (MMPs), fibroblast growth factor (FGF) and chemokine C-C ligand 1 (CCL1), 2 (CCL2), 5 (CCL5) and 17 (CCL17). Parts of the figure are drawn using pictures from Servier Medical Art (https://smart.servier.com, (accessed on 18 December 2022).

Figure 3

Timeline indicating immunotherapies approved by the FDA for the treatment of patients affected by melanoma (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm, (accessed on 20 December 2022).

Figure 4

Classification and chemical structure of phenolic compounds. Basic skeleton structure of flavonoids and their principal classes are shown.

Figure 5

Main secondary metabolites with immunomodulatory activity on melanoma addressed in this paper.

Figure 6

Chemical structure of methylxanthines: caffeine (1,3,7-trimethyl-), theophylline (1,3-dimethyl-) and theobromine (3,7-dimethyl-)xanthine.

Figure 7

Chemical structure of principal flavonoids discussed in this section. EGCG, epigallocatechin gallate.

Figure 8

Mechanisms of action of curcumin.

Figure 9

Mechanisms of action on melanoma and immune cells. Parts of the figure are drawn using pictures from Servier Medical Art (https://smart.servier.com, (accessed on 20 January 2023)).