T-cell mediated anti-tumor immunity after photodynamic therapy: why does it not always work and how can we improve it?

Abstract

Photodynamic therapy (PDT) uses the combination of non-toxic photosensitizers and harmless light to generate reactive oxygen species that destroy tumors by a combination of direct tumor cell killing, vascular shutdown, and activation of the immune system. It has been shown in some animal models that mice that have been cured of cancer by PDT, may exhibit resistance to rechallenge. The cured mice can also possess tumor specific T-cells that recognize defined tumor antigens, destroy tumor cells in vitro, and can be adoptively transferred to protect naïve mice from cancer. However, these beneficial outcomes are the exception rather than the rule. The reasons for this lack of consistency lie in the ability of many tumors to suppress the host immune system and to actively evade immune attack. The presence of an appropriate tumor rejection antigen in the particular tumor cell line is a requisite for T-cell mediated immunity. Regulatory T-cells (CD25+, Foxp3+) are potent inhibitors of anti-tumor immunity, and their removal by low dose cyclophosphamide can potentiate the PDT-induced immune response. Treatments that stimulate dendritic cells (DC) such as CpG oligonucleotide can overcome tumor-induced DC dysfunction and improve PDT outcome. Epigenetic reversal agents can increase tumor expression of MHC class I and also simultaneously increase expression of tumor antigens. A few clinical reports have shown that anti-tumor immunity can be generated by PDT in patients, and it is hoped that these combination approaches may increase tumor cures in patients.

Antimicrobial photodynamic therapy in skin wound healing: A systematic review of animal studies

“…First, it has a significant impact on neutrophil activation: after PDT, neutrophils gather in the target lesions. This reaction is due in part to upregulated TNF‐α expression after PDT . PDT also induces the release by various cells of pro‐inflammatory cytokines, which activate other cells of the innate immune system and induce monocytes, macrophages, and mast cells to accumulate in the PDT‐treated lesion.…”

“…This reaction is due in part to upregulated TNF-α expression after PDT. 56 PDT also induces the release by various cells of proinflammatory cytokines, which activate other cells of the innate immune system 57 and induce monocytes, macrophages, and mast cells to accumulate in the PDT-treated lesion. This in turn activates CD8+ T cells and eliminates damaged cells and tissues.…”

Engineering of relevant photodynamic processes through structural modifications of metallotetrapyrrolic photosensitizers

“…The insult mediated by oxidative stress at the targeted tissue triggers a complex multifactorial response engaging host defense mechanisms associated with the inflammatory process that participate in the eradication of the treated tumor and involve many elements of the innate and adaptive immune systems [5,21,22,28,274,275]. During photodynamic action, neutrophils are among the first cells recruited to the illuminated area [276].…”

“…CT26WT) or the CT26.CL25 analogue characterized by secretion of the bacterial protein beta-galactosidase results in completely curative effects and resistance to rechallenge only in case of mice bearing antigen expressing tumors (CT26.CL25). Moreover, studies on bilateral tumor animal-model revealed that the immune response against the CT26.CL25 tumor after verteporfin-PDT of one tumorwas sufficiently strong to inhibit further progression of the contralateral tumor[27,275]. The response to PDT may vary not only with the type of photosensitizer, its physicochemical properties and intracellular localization, but also with the DLI, light dose and total light fluence delivered, as well as with the experimental model, cell type and its genetic or metabolic potential.…”

Anti-tumor immunity of BAM-SiPc-mediated vascular photodynamic therapy in a BALB/c mouse model

“…56,57 VPDT-mediated anti-tumor immunity relies heavily on the activity of T cells. 58 The involvement of T cells in BAM-SiPc-VPDT-induced anti-tumor immunity was verified in the present study by (i) the presence of tumor-infiltrating CD4 1 and CD8 1 T cells ( Figure 5a); (ii) the presence of cytotoxic lymphocytes against CT26 cells ( Figure 5b); (iii) the secretion of T-cell-activating Th1 cytokines (IFN-c and TNF-a) by splenocytes obtained from the VPDT-cured mice when co-cultured with CT26 cells (Figure 4); and (iv) the loss of anti-tumor immunity in the VPDT-cured mice after the depletion of T cells (Figure 5c). …”