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Page 8 of 20 dos Santos et al. J Cancer Metastasis Treat 2019;5:25 I http://dx.doi.org/10.20517/2394-4722.2018.83

lymphocytes to attack cancer cells. The goal of immunotherapy is to generate a robust immune response,
stimulating the endogenous cytotoxic lymphocytes to eradicate tumor cells and ultimately achieve long-
[67]
term anticancer immunity . Therefore, the ideal cancer treatment should involve the direct cytotoxic
action on tumor cells with potential to stimulate the immune system based on the immune-recognition of
[68]
danger signals emitted by dying cells . In a typical immune response, antigens are captured by dendritic
cells (DCs), which then mature and present antigenic peptides to T cells in lymph nodes, generating effector
T cells that migrate towards sites of infection, inflammation or injury. IFN-γ and GM-CSF are central to the
process of DC maturation and macrophage activation. DCs in turn release cytokines, like IL-1β, IL-6, IL-
12 or TNF, that shape the Natural Killer cell (NK) and T cell responses. T cells CD4+ and CD8+, together
with NK cells, can receive survival signals and stimulation from IL-2, leading to full effector activities, and
produce additional IFN-γ. Normal immune regulation involves cytokines like IL-10 and TGF-β to limit the
activity of T cells and macrophages and reduce inflammation, terminating immune responses and protecting
[67]
the host from immune-mediated damage . Some tumors appear to have somehow managed to avoid
detection by the various arms of the immune system or have been able to limit the extent of immunological
[69]
killing, thereby evading their eradication .

The best way to reestablish an immune system response against tumors is by eliciting, therapeutically,
a cancer cell death pathway that is accompanied by high immunogenicity and is possibly able to inhibit
or reduce the influence of the pro-tumorigenic cytokine signaling. Over the last years, several studies
demonstrated that few selected anti-cancer therapeutic approaches are able to induce a promising kind of
[70]
cancer cell demise called immunogenic cell death (ICD) . The concept of ICD has been introduced to
describe a cell death modality that stimulates an immune response against antigens coming from dead cells.
After exposure to certain cytotoxic ICD-agents, changes in the composition of the cell surface promote the
[71]
exposure or release of mediators, the so-called damage associated molecular patterns (DAMPs) . These
[72]
signals are thus further recognized by DCs to stimulate the presentation of tumor antigens to T cells . It
has emerged that initiating a tumor cell death modality associated with the activation of signaling pathways
[73]
that release DAMPs markedly increases the immunogenicity of dying cancer cells . Up to now, the main
DAMPs involved in ICD include surface-exposed calreticulin (CRT), surface-exposed heat shock protein
(HSP) 70 and 90, secreted adenosine triphosphate and passively released high-mobility group box 1 (HMGB1) [71,74] .
Many conventional anticancer treatments, that include chemotherapies, radiotherapies and target therapies
have had their immunogenic potential evaluated, but only a few of them have been characterized as ICD-
[72]
inducers . This exclusive inducer-induction relationship exists because ICD requires, as a pre-requisite,
induction of reactive oxygen species (ROS)-based ER stress, where ROS may or may not be mainly ER-
[75]
directed . As a ROS-inducer therapy, the potential of PDT in stimulating ICD seems to be quite probable,
and has been tested.

Preclinical studies have shown that in contrast to the effects of traditional therapies, low-dose PDT regimens
can induce anti-tumor immunity, and these can be combined with high-dose PDT to achieve local tumor
[76]
control with the immune suppression of distant disease . The potential mechanisms of PDT immune
stimulation involve the acute inflammatory response following PDT, which might increase the presentation of
tumor antigens to activate DC, and their homing in to regional and peripheral lymph nodes, thus ultimately
stimulating CD8+ cytotoxic T cells and NK cells, accompanied by immune memory and the suppression
of any subsequent tumor growth upon a second challenge. The degree of acute inflammation induced by
PDT has been reported to be regimen dependent and to correlate with the extent of the induced vascular
damage. PDT regimens that result in rapid cell death (within 1 h of treatment) and maximal tissue damage
were demonstrated to cause minimal acute inflammation, presumably because of vascular shutdown, which
would prevent neutrophil infiltration and systemic release of cytokines. In contrast, regimens that cause
diffuse tumor damage should allow neutrophil infiltration followed by induction of expression and release of
[77]
inflammatory mediators critical for enhancement of anti-tumor immunity . Ongoing studies are focused