Table 1.

Selected pathways for immune modulation and homeostasis.

Pathway	Comment
T-cell activation checkpoints: -PD–1–PDL1 -CTLA4–CD80/86 -KIR–MHC -LAG3–MHC -TIM3–Gal9 -BTLA–HVEM -NKG2A–HLA–E	The first element in each pair of this category except NKG2A is located on the T cell, and ligand interaction results in direct down-regulatory cell signaling in the T cell [17]. NKG2A is the ligand for HLA-E and down regulates NK-cell activity [22]
T-cell activation stimulators: -CD–27–CD70 -CD–28–CD80/86 -CD40L–CD40 -GITR–GITRL -CD137–41BBL -CD134–OX40L -ICOS–B7RP1	The first element of the pair in this activator list is on the T cell. Ligand binding promotes T-cell activation, except for CD40L which stimulates APC leading to indirect T-cell activation [17]
Pathogen associated molecular patterns: -Toll-like receptor family -Nucleic acid-TLR3,7,8,9 -LPS–TLR4 -Flagellin–TLR5 -Lipopeptides–TLR1,2	A primary interface between intrinsic and adaptive immunity is mediated by recognition by local cells of foreign materials. Characteristic molecular patterns including microbial DNA/RNA, microbial cell wall elements and microbial glycolipid structures bind these receptors and trigger immune stimulator cytokine activation [23]. Toll-like receptor agonists may be useful for combination with immune modulatory antibodies
Metabolic T-cell modulators: -A2aR–adenosine -indoleamine oxidase	Adenosine accumulates at the site of cell death and is stimulatory to Treg cells, thus down regulating inflammatory sites [24]. Tryptophan is a needed amino acid for T-cell growth, indoleamine oxidase metabolizes tryptophan and is overexpressed in tumors facilitating immune escape [25]
Cell types with immune-modulatory function: -Plasmacytoid dendritic cells -Regulatory T cells -Myeloid derived suppressor cells -Macrophage -Mast Cell -Fibroblasts	Many cells involved in coordinating a primary immune response and facilitating healing are capable of producing inflammation limiting cytokines, promoting angiogenesis, collagen synthesis and scar tissue formation. Tumors can find growth advantage by expressing factors that favor a ‘healing microenvironment’. These cell types thus can be tumor promoting in states of chronic inflammatory wound healing but can also mediate antitumor effects when armed with a specific antibody [26,27]
Immune stimulatory cytokines: -IL-1 -IFN-α -TNF-α -IL-6, -IL-12 -IL-18	A few select cytokines that are central to activating an immune response and favoring cell-mediated T-cell immunity are listed here; however many other cytokines influence the immune balance and may be highly relevant to effective cancer immunotherapy [28]
Immune suppressive cytokines: -TGF-β, -IL-10	There are many other factors and cytokines that also influence the balance of immunity, however IL-10 and TGF-β are especially well characterized in this regard [28]
Effector cell chemokines: -MCP-1 -CCL5 -CCL10	Chemokines facilitate local accumulation of effector cells including activated T cells, NK cells and inflammatory monocytes [21]
Suppressor cell chemokines: -CCL22	CCL22 is locally chemotactic to Tregs; there are other chemokines that are chemotactic to immune-regulatory cell phenotypes that may also be targets [21]