The Course of Immune Stimulation by Photodynamic Therapy: Bridging Fundamentals of Photochemically Induced Immunogenic Cell Death to the Enrichment of T‐Cell Repertoire

Abstract

Photodynamic therapy (PDT) is a potentially immunogenic and FDA‐approved antitumor treatment modality that utilizes the spatiotemporal combination of a photosensitizer, light and oftentimes oxygen, to generate therapeutic cytotoxic molecules. Certain photosensitizers under specific conditions, including ones in clinical practice, have been shown to elicit an immune response following photoillumination. When localized within tumor tissue, photogenerated cytotoxic molecules can lead to immunogenic cell death (ICD) of tumor cells, which release damage‐associated molecular patterns and tumor‐specific antigens. Subsequently, the T‐lymphocyte (T cell)–mediated adaptive immune system can become activated. Activated T cells then disseminate into systemic circulation and can eliminate primary and metastatic tumors. In this review, we will detail the multistage cascade of events following PDT of solid tumors that ultimately lead to the activation of an antitumor immune response. More specifically, we connect the fundamentals of photochemically induced ICD with a proposition on potential mechanisms for PDT enhancement of the adaptive antitumor response. We postulate a hypothesis that during the course of the immune stimulation process, PDT also enriches the T‐cell repertoire with tumor‐reactive activated T cells, diversifying their tumor‐specific targets and eliciting a more expansive and rigorous antitumor response. The implications of such a process are likely to impact the outcomes of rational combinations with immune checkpoint blockade, warranting investigations into T‐cell diversity as a previously understudied and potentially transformative paradigm in antitumor photodynamic immunotherapy.

Type I photosensitizers based on phosphindole oxide for photodynamic therapy: apoptosis and autophagy induced by endoplasmic reticulum stress

“…As described above, the antitumor effect of PDT involves not only eliminating the local primary tumor but also triggering systemic antitumor immunity, through inammatory response or immunogenic cell death (ICD), against circulating, metastatic or recurrent tumors to meet the demand for long-term management. [33][34][35] ICD is obligatorily and critically preceded by calreticulin exposure resulting from ROS-based endoplasmic reticulum (ER) stress. 36,37 So, ICD inducers are classied into two categories: non-ER-targeting ones with collateral effects and ER-targeting ones with direct effects.…”

Dendritic Cells and Immunogenic Cancer Cell Death: A Combination for Improving Antitumor Immunity

“…Photochemical processes are generated upon irradiation of tumor sites with a PS-exciting light of specific wavelength after administration of the photosensitizer agent (PS). PS toxicity is not appreciated unless oxidative stress occurs in response to its activation [125,141]. In addition to eliciting direct cytotoxic effects [142][143][144][145][146][147] and vascular damage [148], PDT also induces immunological reactions [20,[149][150][151].…”

Photodynamic therapy, priming and optical imaging: Potential co-conspirators in treatment design and optimization — a Thomas Dougherty Award for Excellence in PDT paper

“…In addition to the direct toxicity and death that the PDT process (vascular or cellular) provides, there is an additional sub-lethal photochemistry induced biological effect which primes the cellular, stromal and/ or vascular microenvironment for subsequent treatment with other modalities and is referred to as photodynamic priming (PDP). An exciting outcome of PDP is the sensitization of tumors for enhanced secondary therapies, such as immune-, chemo-therapy, and other inhibitory therapies, including receptor tyrosine kinase inhibition (RTKi) (discussed in a later section) [18,[34][35][36][37][38][39][40][41][42][43] making PDP an enabler of the more commonly used therapies. The various mechanisms associated with PDT are briefly discussed in this section.…”