Stimulation of anti-tumor immunity by photodynamic therapy

Abstract

Photodynamic therapy (PDT) is a rapidly developing cancer treatment that utilizes the combination of nontoxic dyes and harmless visible light to destroy tumors by generating reactive oxygen species. PDT produces tumor-cell destruction in the context of acute inflammation that acts as a 'danger signal' to the innate immune system. Activation of the innate immune system increases the priming of tumor-specific T lymphocytes that have the ability to recognize and destroy distant tumor cells and, in addition, lead to the development of an immune memory that can combat recurrence of the cancer at a later point in time. PDT may be also successfully combined with immunomodulating strategies that are capable of overcoming or bypassing the escape mechanisms employed by the progressing tumor to evade immune attack. This article will cover the role of the immune response in PDT anti-tumor effectiveness. It will highlight the milestones in the development of PDT-mediated anti-tumor immunity and emphasize the combination strategies that may improve this therapy.

Figure 1. Anti-tumor mechanisms of photodynamic therapy

Jablonski diagram illustrates the absorption of light by photosensitizer ground state to form a short-lived excited singlet state that can lose energy by fluorescence, internal conversion to heat, or can undergo intersystem crossing to long-lived PS triplet state that can carry out photochemistry. Subsequently this photochemistry leads to the local production of reactive oxygen species that are cytotoxic to tumor and endothelial cells. HSP: Heat-shock protein; hv: Light; ISC: Intersystem crossing; PDT: Photodynamic therapy; S₀: Ground state; S₁: First excited singlet state; S₂: Second excited singlet state; T₁: First excited triplet state.

Figure 2. Clinically approved photosensitizers for photodynamic therapy

5-ALA: 5-aminolevulinic acid; BPD-MA: Benzoporphyrin derivative monoacid ring A; HP: Hematoporphyrin; mTHPC: m-tetrahydroxyphenylchlorin.

Figure 3. Photodynamic therapy of tumors leads to the development of local inflammation mediated by the localized release of danger signals, cytokines and derivatives of arachidonic acid

The infiltration of the treated area by various cells of the immune system follows. EC: Endothelial cell; HSP: Heat-shock protein; hv: Light; PMN: Polymorphonuclear neutrophil; TBX: Thromboxane. Adapted with permission from [25].

Figure 4. Photodynamic therapy-induced local inflammation leads to the development of systemic immunity

Antigens released from PDT-treated tumor cells are phagocytosed by DCs and presented to naive T cells in regional lymph nodes. Activated T cells return to the circulation and then track down and destroy tumors. BCG: Bacillus Calmette–Guérin; C.P.: Corynebacterium parvum; DC: Dendritic cell; G-CSF: Granulocyte colony-stimulating factor; GM-CSF: Granulocyte-macrophage colony-stimulating factor; hv: Light; MCWE: Mycobacterium cell wall extract; PDT: Photodynamic therapy; SPG: Schizophylan. Adapted with permission from [25].

Figure 5. Local activation of the innate immune system can be strongly potentiated by strategies that facilitate better activation of dendritic cells, macrophages or neutrophils

Intratumoral injection greatly enhances the effectiveness of combination strategies. DC: Dendritic cell; hv: Light; PDT: Photodynamic therapy. Adapted with permission from [25].