Immune response after photodynamic therapy increases anti-cancer and anti-bacterial effects

Table 1 Milestone studies on effects of photodynamic therapy affecting the immune system

Immune components	Immunomodulatory effect of PDT	Ref.
Pro-inflammatory cytokines	Production of pro-inflammatory cytokines after PDT in vivo	[26]
Macrophages	First evidence of cytokine production by PDT-treated macrophages in vivo	[107]
Dendritic cells	DCs can efficiently phagocytose PDT-treated tumor cells in in vivo experiments. Immature DCs administered in combination with PDT produce effective antitumor response in vivo	[38,108]
NKs	Role of NKs in immune response after PDT, control of distant untreated tumors	[43]
Neutrophils	Evidences that neutrophils have a crucial role in the PDT response in vivo	[30,109]
Memory immunity	First demonstration that a specific antitumor memory immunity is induced after PDT: resistance to tumor rechallenge in animals cured by PDT	[110]
T lymphocytes, memory immunity	Essential role of host T lymphocytes in immune response after PDT: curative effect of PDT in immune-competent Balb/c mice, but not in immune-suppressed scid mice. Adoptive transfer of splenocytes from PDT-cured mice to scid mice confers resistance to tumor rechallenge	[8,111]
Treg	Evidences for the role of Treg in inhibiting the immune response after PDT	[77]
Patient lymphocytes	First demonstration that an antigen-specific immune response can be observed after PDT	[65]

PDT: Photodynamic therapy; DCs: Dendritic cells; NKs: Natural killer cells; Treg: T regulatory cells.

Table 2 Damage-associated molecular pattern molecules that may be released or exposed on the outer leaflet of dying tumor cells after photodynamic therapy

DAMP	Function	Ref.
HSP60, HSP70, HSP90, gp96, GRP94, GRP78	Molecular chaperones that normally reside in intracellular regions/organelles, but under stress they are exposed on the damaged cell surface and prime immunomodulatory processes	[11,21,22,112]
Calreticulin	Calcium binding protein located in intracellular regions/organelles (mostly in ER), but under stress its presence on the PM is augmented. On the PM it acts as “danger signal” and increases the immunogenicity of the dying cells	[11,112]
ATP	High-energy molecule, normally intracellular, but can be released by necrotic and apoptotic cells under particular stresses. Extracellular ATP has the ability to help in chemoattraction of immune cells	[12,112]
Phosphatidylserine	When cells are damaged/dying, phosphatidylserine is transposed from the inner to the outer leaflet and acts as an “eat me” signal by interacting with multiple immune cells receptors, mediating efficient phagocytosis and anti-inflammatory responses	[112,113]
High mobility group box-1	Nuclear chromatin-binding protein; it has prominent cytokine-line properties and when released by dying cells tends to stimulate immune cells to produce various pro-inflammatory cytokines	[11,112]
Calgranulin family members (S100A8, S100A9, S100A12)	Calcium-binding proteins; when released by necrotic cells they act as “find me” signals attracting various immune cells and interacting with immune cell receptor (TLR4/RAGE) to induce the secretion of pro-inflammatory cytokines	[11,112,114]
Cross-linked dimer of ribosomal protein S19	Constituent of small ribosomal subunit; when released by necrotic cells it acts as a chemotactic factor for attracting various immune cells	[11,112]

DAMPs: Damage-associated molecular patterns; ER: Endoplasmatic reticulum; PM: Plasma membrane; HSP: Heat shock protein; GRP: Glucose-regulated protein; ATP: Adenosine triphosphate; TLR4: Toll-like receptor 4; RAGE: Receptor for advanced glycation end-products.

Table 3 Common features of T regulatory cells

Features of Treg	Ref.
Phenotypic and functional specialization	[66-68]
Treg are CD4+CD25+FoxP3+ immunosuppressive T cells. They are important for the maintenance of the immune homeostasis and involved in both autoimmune disease and cancer	[71,72]
Cells subpopulations
Treg are generally classified into nTreg and iTreg. The former are found in the thymus and thought to have T-cell receptors that recognizes self-antigens, therefore important in the prevention of autoimmune disease, the latter can be induced and differentiate in the periphery, i.e., upon influence by TGF-β in the tumor microenvironment	[69,70]
Immunosuppressive mechanisms
Treg are thought to mediate their immunosuppressive effects by multiple mechanisms, among which
Secretion of immunosuppressive cytokines
High affinity binding of his CTLA-4 receptor to B7-1 and B7-2 costimulatory molecules on antigen presenting cells and transmission of inhibitory signals
Role of Treg in anti-tumor immunity	[71,73-75]
Treg are known to inhibit the generation of immune responses against tumors. Treg depletion in vivo facilitates tumor eradication and enhances-anti-tumor immunity

nTreg: Natural Treg; iTreg: Induced Treg; CTLA-4: Cytotoxic T-lymphocyte antigen 4; Treg: T regulatory cells; TGF: Transforming growth factor.