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Treatment of pancreatic cancer is faced with great difficulties and challenges due to high lethality and metastasis. Synergism of targeted therapy and immunotherapy has been considered as ideal strategy to both eliminate primary tumors and control metastases. For the treatment of advanced pancreatic cancer, we demonstrated a local photothermal therapy (PTT) following administration of monoclonal antibody of programmed death ligand 1 (αPD-L1). Fe2P nanorods were employed as a Fenton agent and photothermal agent, which modified with DSPE-PEG2000-Mal for improved biocompatibility and Mal mediated-antigen presentation. Under a low dose laser irradiation at 980 nm, Fe2P-PEG-Mal nanorods (NRs) mediated PTT could induce immunogenic tumor cell death that can cause dendritic cells (DCs) infiltration and maturation. In a bilateral pancreatic tumor model, the local treatment of NRs-PTT on primary tumor could cause the increased infiltration of cytotoxic T lymphocytes (CTLs) and decreased residential of M2 macrophages in untreated distal tumors. Furthermore, subsequently intervened αPD-L1 could enhance cell death triggered by CTLs in distal tumors through reversing immunosuppression. An orthotopic pancreatic tumor model was used to further confirm the therapeutic outcome. Finally, the combination of NRs based PTT and αPD-L1 based immunotherapy was able to significantly eliminate orthotopic pancreatic tumors and reduce mesentery metastases. Thus, the strategy may provide a more effective treatment for pancreatic cancer.

Targeted therapy and immunotherapy in combination is considered the ideal strategy for treating metastatic cancer, as it can eliminate the primary tumors and induce host immunity to control distant metastases. Phototherapy, a promising targeted therapy, eradicates primary tumors using an appropriate dosage of focal light irradiation, while initiating antitumor immune responses through induced immunogenic tumor cell death. Recently, phototherapy has been employed to improve the efficacy of immunotherapies such as chimeric antigen receptor T-cell therapy and immune checkpoint inhibitors. Phototherapy and immunoadjuvant therapy have been used in combination clinically, wherein the induced immunogenic cell death and enhanced antigen presentation synergy, inducing a systemic antitumor immune response to control residual tumor cells at the treatment site and distant metastases. This review summarizes studies on photo-immunotherapy, the combination of phototherapy and immunotherapy, especially focusing on the development and progress of this unique combination from a benchtop project to a promising clinical therapy for metastatic cancer.

Development of bioresponsive theranostic nanoparticles to enhance cancer diagnostics and control cancer metastasis is highly desirable. In this study, we developed such a bioresponsive theranostic nanoparticle for synergistic photoimmunotherapy. In particular, these nanoparticles were constructed by embedding indocyanine green (ICG) into Mn2+-doped amorphous calcium carbonate (ACC(Mn)) nanoparticles, followed by loading of the Toll-like-receptor-7 agonist imiquimod (IMQ). The IMQ@ACC(Mn)-ICG/PEG nanoparticles respond to the acidic pH of the tumor microenvironment (TME) and co-deliver ICG and IMQ into the tumor. Selective phototherapy was achieved upon activation using a near-infrared laser. In the presence of IMQ and arising from phototherapeutically treated tumor cells, tumor-associated antigens give rise to a strong antitumor immune response. Reversal of the immunosuppressive TME via H+ scavenging of the tumor through ACC nanoparticles effectively inhibits tumor metastases. Moreover, the combination of ICG and Mn2+ also serves as an advanced contrast agent for cancer multimode imaging. Overall, these bioresponsive nanoparticles provide a promising approach for cancer theranostics with promising potential for future clinical translation.

Melanoma is one of the deadliest malignancies with a high risk of relapse and metastasis. Long-term, tumor-specific, and systemic immunity induced by local intervention is ideal for personalized cancer therapy. Laser immunotherapy (LIT), a combination of local irradiation of laser and local administration of an immunostimulant, was developed to achieve such an immunity. Although LIT showed promising efficacy on tumors, its immunological mechanism is still not understood, especially its spatio-temporal dynamics. Methods: In this study, we investigated LIT-induced immunological responses using a 980-nm laser and a novel immunostimulant, N-dihydrogalactochitosan (GC). Then we followed the functions of key immune cells spatially and temporally using intravital imaging and immunological assays. Results: Immediately after LIT, GC induced a rapid infiltration of neutrophils which ingested most GC in tumors. The cytokines released to the serum peaked at 12 h after LIT. Laser irradiations produced photothermal effects to ablate the tumor, release damage-associated molecular patterns, and generate whole-cell tumor vaccines. LIT-treated tumor-bearing mice efficiently resisted the rechallenged tumor and prevented lung metastasis. Intravital imaging of tumor at rechallenging sites in LIT-treated mice revealed that the infiltration of tumor-infiltrating lymphocytes (TILs) increased with highly active motility. Half of TILs with arrest and confined movements indicated that they had long-time interactions with tumor cells. Furthermore, LIT has synergistic effect with checkpoint blockade to improve antitumor efficacy. Conclusion: Our research revealed the important role of LIT-induced neutrophil infiltration on the in situ whole-cell vaccine-elicited antitumor immune response and long-term T cell immune memory.

Pancreatic cancer (PC) is the most lethal malignancy due to its high metastatic ability and poor drug permeability. Here, a synergized interventional photothermal-immunotherapy strategy was developed with imaging guidance and temperature monitoring by magnetic resonance imaging (MRI) technique, for the local treatment of metastatic PC. A tumor microenvironment (TME)-responsive nanoplatform was fabricated via coating of DSPE-PEG and indocyanine green (ICG) onto imiquimod (IMQ) loaded amorphous iron oxide nanoparticles (IONs). This unique nanoplatform, IMQ@IONs/ICG, served as a contrast agent for MRI, a drug delivery vehicle for IMQ and ICG, and a catalyst for TME modulation. The biodegradable IMQ@IONs/ICG was also non-toxic, and improved the penetration of the loaded drugs in PC to maximize thermal ablation of the tumor and minimize damage to the surrounding healthy tissue. For the treatment of aggressive, metastatic Panc02-H7 pancreatic tumors in mice, ION-assisted MRI was employed to guide the administration of interventional photothermal therapy (IPTT) and monitor the temperature distribution in target tumor and surrounding tissue during treatment. The local IPTT treatment induced in situ immunogenic cell death (ICD), and, in combination with released IMQ, triggered a strong antitumor immunity, leading to decreased metastases and increased CD8+ in spleen and tumors. With precise local treatment and monitoring, treated primary tumors were completely eradicated, mesentery metastases were dramatically reduced, and the survival time was significantly prolonged, without damage to normal tissue and systemic autoimmunity. Overall, this synergistic strategy represents a promising approach to treat PC with significant potential for clinical applications. STATEMENT OF SIGNIFICANCE: Pancreatic cancer (PC) is one of the most lethal malignancies because it is non-permeable to drugs and highly metastatic. In this study, we designed a tumor microenvironment-responsive amorphous iron oxide nanoplatform (ION) to co-deliver photothermal agent (ICG) and toll-like-receptor-7 agonist (IMQ). This biodegradable nanoplatform IMQ@IONs/ICG improved the penetration of the loaded drugs in pancreatic tumor. With MR imaging guidance and temperature monitoring, the precise interventional photothermal therapy on mouse Panc02-H7 orthotopic tumors releases tumor antigens to initiate tumor-special immune responses, amplified by the released IMQ. Our results demonstrate that IMQ@IONs/ICG overcomes the obstacle of drug delivery to pancreatic tumors, and when combined with photothermal therapy, induces a systemic antitumor immunity to control metastatic tumors.

Metastasis is the major cause of cancer-death. Checkpoint inhibition shows great promise as an immunotherapeutic treatment for cancer patients. However, most currently available checkpoint inhibitors have low response rates. To augment the antitumor efficacy of checkpoint inhibitors, such as CTLA-4 antibodies, a single-walled carbon nanotube (SWNT) modified by a novel immunoadjuvant, glycated chitosan (GC), was used for the treatment of metastatic mammary tumors in mice. We treated the primary tumors by intratumoral administration of SWNT-GC, followed with irradiation with a 1064-nm laser to achieve local ablation through photothermal therapy (PTT). The treatment induced a systemic antitumor immunity which inhibited lung metastasis and prolonged the animal survival time of treated. Combining SWNT-GC-laser treatment with anti-CTLA-4 produced synergistic immunomodulatory effects and further extended the survival time of the treated mice. The results showed that the special combination, PTT + SWNT-GC + anti-CTLA, could effectively suppress primary tumors and inhibit metastases, providing a new treatment strategy for metastatic cancers.

Immunotherapies have been established as safe and efficient modalities for numerous tumor treatments. The lymphatic system, which is an important system, can modulate the immune system via a complex network, which includes lymph nodes, vessels, and lymphocytes. With the deepening understanding of tumor immunology, a plethora of immunotherapies, which include vaccines, photothermal therapy, and photodynamic therapy, have been established for antitumor treatments. However, the deleterious off-target effects and nonspecific targeting of therapeutic agents result in low efficacy of immunotherapy. Fortunately, nanoparticle-based approaches for targeting the lymphatic system afford a unique opportunity to manufacture drugs that can simultaneously tackle both aspects, thereby improving tumor treatments. Over the past decades, great strides have been made in the development of DC vaccines and nanomedicine as antitumor treatments in the field of lymphatic therapeutics and diagnosis. In this review, we summarize the current strategies through which nanoparticle technology has been designed to target the lymphatic system and describe applications of lymphatic imaging for the diagnosis and image-guided surgery of tumor metastasis. Moreover, improvements in the tumor specificity of nanovaccines and medicines, which have been realized through targeting or stimulating the lymphatic system, can provide amplified antitumor immune responses and reduce side effects, thereby promoting the paradigm of antitumor treatment into the clinic to benefit patients.

Objective: To confirm the feasibility and accuracy of the method for evaluating blood supply and embolization rate of liver cancer based on I-flow software through animal experiments and clinical study. Methods: Rabbits underwent selective angiography under different perfusion conditions in the same kidney. The blood supply level was evaluated by I-flow software method. The results were analyzed for coefficient of variation. Thirty patients with liver cancer who underwent selective hepatic artery embolization were enrolled. The mathematical methods and 3 diagnostic specialists were used to evaluate the preoperative blood supply level and embolization rate. The results were recorded and the results were tested for consistency. Results: Animal experiments confirmed that the blood supply level analysis method designed by the research team was consistent under different contrast conditions (including total contrast agent, contrast medium perfusion rate, and limiting pressure) (coefficient of variation: 8.55%). The mathematical calculation results of preoperative blood supply level and embolization ratio of liver cancer are consistent with the average value of visual judgment results of diagnostic experts. (Preoperative blood supply level: concordance coefficient = 0.284, P = 0.003; embolization ratio: concordance coefficient = 0.218, P = 0.011). Conclusion: Based on I-flow software, the mathematical calculation method designed by this research group can effectively estimate the preoperative blood supply level of liver cancer and the embolization rate of single vascular embolization treatment, which can provide reliable data support for embolization treatment of liver cancer.

Pancreatic cancer is an extremely malignant disease with high mortality rate. Currently there is no effective therapeutic strategy for highly metastatic pancreatic cancers. Laser immunotherapy (LIT) is a combination therapeutic approach of targeted phototherapy and immunotherapy, which could destroy treated primary tumors with elimination of untreated metastases. Here, we investigate the antitumor immune response of LIT on a highly aggressive phenotype Pnac02-H7 mouse pancreatic tumor model. LIT affords a remarkable efficacy in suppressing tumor growth in pancreatic tumors in mice, and results in complete tumor regression in many cases. LIT could synergize targeted phototherapy and immunological effects of immunoadjuvant, which represent a promising treatment modality to induce systemic antitumor response through a local intervention, paving the way for the treatment of highly metastatic pancreatic cancers.

The development of therapeutic methods that can effectively delay tumor growth, inhibit tumor metastases, and protect the host from tumor recurrence still faces challenges. Nanoparticle-based combination therapy may provide an effective therapeutic strategy. Herein, we show that bovine serum albumin (BSA)-bioinspired gold nanorods (GNRs) were loaded with an immunoadjuvant for combined photothermal therapy (PTT) and immunotherapy for the treatment of melanoma. In this work, cetyltrimethylammonium bromide (CTAB)-coated GNRs were successively decorated with polyethylene glycol (PEG) and BSA, and loaded with an immunoadjuvant imiquimod (R837). The synthesized mPEG-GNRs@BSA/R837 nanocomplexes under near-infrared (NIR) irradiation could effectively kill tumors and trigger strong immune responses in treating metastatic melanoma in mice. Furthermore, the nanocomplex-based PTT prevented lung metastasis and induced a strong long-term antitumor immunity to protect the treated mice from tumor recurrence. The nanocomplex-based PTT in combination with immunotherapy may be potentially employed as an effective strategy for the treatment of melanoma and other metastatic cancers.

Immunotherapy has become a promising modality for melanoma, especially using checkpoint inhibitors, which revive suppressed T cells against the cancer. Such inhibitors should work better when combined with other treatments which could increase the number and quality of anti-tumor T cells. We treated one patient with advanced (stage IV) melanoma, using the combination of laser immunotherapy (LIT), a novel immunological approach for metastatic cancers that has been shown to stimulate adaptive immunity, and ipilimumab. The patient was treated with LIT, followed with one course of ipilimumab 3 months after the beginning of LIT. After LIT treatment, all treated cutaneous melanoma in head and neck cleared completely. After the application of ipilimumab, all the tumor nodules in the lungs decreased. The patient had remained tumor free for one year. While anecdotal, the responses seen in this patient support the hypothesis that laser immunotherapy increases the number and quality of anti-tumor T cells so that ipilimumab and other checkpoint inhibitors are more effective in enhancing the therapeutic effects. Picture: Schematic of treatment using laser immunotherapy and ipilimumab on a stage IV melanoma patient.

Photoimmunotherapy has attracted much attention recently for the treatment of metastatic tumors. The development of smart nanocomposites for imaging-guided therapies are needed to improve the efficacy of cancer treatment. Herein, a PEGylated nanocomposite was developed for photothermal-immunotherapy. In particular, this nanocomposite was formulated by hybridizing Fe(3)O(4) nanoparticles (FNPs) with reduced-graphene oxide (rGO) through electrostatic interaction, modified by PEG-NH(2) on the surface of FNPs/rGO. The FNPs/rGO-PEG nanocomposites are excellent agents for photothermal therapy (PTT) under irradiation by an 805-nm laser. This nanocomposite could promote the activity of the host antitumor immune response efficiently because of the reduction of tumor-associated macrophages by the incorporation of FNPs. In our experiments, we observed FNPs/rGO-PEG based PTT induced immunogenic cell death accompanied by release of danger-associated molecular patterns. We also found that FNPs/rGO-PEG + laser irradiation of animal tumors could activate dendritic cells (DCs) in tumor draining lymph nodes. In vivo antitumor studies revealed that FNPs/rGO-PEG nanocomposites, when combined with laser irradiation, could result in desirable photothermal effects and destroy primary tumors. Moreover, intratumoral injection of FNPs/rGO-PEG nanocomposites into 4T1 orthotopic mouse breast tumors, in combination with near-infrared laser irradiation, significantly increased the median survival time of tumor-bearing animals. FNPs/rGO-PEG nanocomposites also could be used for magnetic resonance imaging, which may lead to a MRI-guided photothermal-immunotherapy for metastatic cancers. This study could lead to a cancer treatment strategy that combines PTT with immunotherapies using FNPs/rGO-PEG nanocomposites.

Fibrotic diseases, such as Dupuytren&rsquo, s contracture (DC), involve excess scar tissue formation. The differentiation of fibroblasts into myofibroblasts is a significant mechanism in DC, as it generates tissue contraction in areas without wound openings, leading to the deposition of scar tissue, and eventually flexing one or more fingers in a restrictive fashion. Additionally, DC has a high recurrence rate. Previously, we showed that N-dihydrogalactochitosan (GC), an immunostimulant, inhibited myofibroblast differentiation in a DC fibroblast culture. Our goal of this study was to expand our previous study to include other DC and normal cell lines and other chitosan derivatives (GC and single-walled carbon nanotube-conjugated GC) to determine the specific mechanism of inhibition. Derivative-incorporated and vehicle control (water) anchored fibroblast-populated collagen matrices (aFPCM) were used to monitor compaction (anchored matrix height reduction) using microscopy and optical coherence tomography (OCT) for six days. Fibroblasts were unable to compact chitosan derivative aFPCM to the same extent as vehicle control aFPCM in repeated experiments. Similarly, chitosan derivative aFPCM contracted less than control aFPCM when released from anchorage. Proliferative myofibroblasts were identified by the presence of alpha smooth muscle actin via myofibroblast proliferative assay. In all tested conditions, a small percentage of myofibroblasts and proliferative cells were present. However, when aFPCM were treated with transforming growth factor-beta 1 (TGF-&beta, 1), all tested samples demonstrated increased myofibroblasts, proliferation, compaction, and contraction. Although compaction and contraction were reduced, there was sufficient tension present in the chitosan derivative aFPCM to allow exogenous stimulation of the myofibroblast phenotype.

Nanoparticle-based combination therapy may provide an effective therapeutic strategy. Herein, we show that bovine serum albumin (BSA)-bioinspired gold nanorods (GNRs) loaded with immunoadjuvant for combined photothermal therapy (PTT) and immunotherapy for treatment of melanoma. In this work, cetyltrimethylammonium bromide (CTAB) coated GNRs were successively decorated with polyethylene glycol (PEG) and BSA, and loaded with an immunoadjuvant imiquimod (R837). The synthesized mPEGGNRs@ BSA/R837 nanocomplexes could significantly induce immune response in vitro. Furthermore, under near-infrared (NIR) irradiation could effectively kill tumor cells. The nanocomplex-based PTT in combination with immunotherapy may be potentially employed as an effective strategy for the treatment of melanoma and other metastatic cancers.

Laser Immunotherapy is a recently-developed treatment for metastatic cancers that synergistically applies photothermal laser irradiation in conjunction with a local immunoadjuvant to induce a host anti-cancer immune response. We have used laser immunotherapy to treat orthotopic pancreatic tumors in mice. In this study, we used magnetic resonance imaging to guide laser immunotherapy for interstitial treatment of metastatic pancreatic tumors in mice. Furthermore, we used MRI to investigate tumor location, guide laser treatment, and monitor the photothermal effects using proton resonance frequency shift thermometry. Our results indicate that laser immunotherapy could be an effective modality for late-stage pancreatic cancer patients, and that MRI thermometry can effectively monitor treatment for guidance.

Immunotherapy shows remarkable efficacy in treating several types of cancer such as melanoma, leukemia, and lung carcinoma, but its therapeutic effect for most solid tumors is still limited. Various cancer therapies, such as chemotherapy, radiotherapy and phototherapy, kill solid tumors through non-inflammatory apoptosis or ablation, rather than making solid tumors immunogenic. As a highly-inflammatory programmed cell death (PCD), pyroptosis provides a great opportunity to alleviate immunosuppression and promote a systemic immune response in treating solid tumors. Herein, by fusing breast cancer membrane onto the poly(lactic-co-glycolic acid) polymeric core, we design a biomimetic nanoparticle (BNP) loaded with indocyanine green (ICG) and decitabine (DCT) for photo-activated cancer cell pyroptosis and solid tumor immunotherapy. The tumor-homing BNP effectively accumulate in tumor with low immunogenicity. ICG in BNP puncture cancer cell membranes induces a sharp cytoplasm Ca2+ concentration increase by low-dose NIR photo-activation, which promotes cytochrome c release followed by caspase-3 activation. DCT up-regulates GSDME expression synergistically via inhibiting DNA methylation, which enhances caspase-3 cleavage to GSDME and causes cancer cell pyroptosis. Finally, photo-activated pyroptosis mediated by BNP induces an impressive systemic antitumor immunity for inhibition of both primary tumor and distant tumors. Overall, pyroptosis-associated BNP shows a novel strategy for solid tumor immunotherapy with high compatibility and wide clinical applicability.

Immunotherapy has been a promising candidate for cancer treatment. The combination of photothermal therapy (PTT) and immunotherapy have shown to cause tumor ablation and induce host immune response. However, this strategy is often hampered by a limited immune response and undesirable immunosuppression. In this work, we developed an immunologically modified nanoplatform, using ovalbumin (OVA)-coated PEGylated MnFe2O4 nanoparticles (NPs) loaded with R837 immunoadjuvant (R837-OVA-PEG-MnFe2O4 NPs) to synergize PTT and immunotherapy for the treatment of breast cancer. The designed R837-OVA-PEG-MnFe2O4 NPs are able to elicit significant immune responses in vitro and in vivo. MnFe2O4 NPs also allowed for a reduction of systemic immunosuppression through downregulation of M2-associated cytokines. More importantly, the R837-OVA-PEG-MnFe2O4 NPs under laser irradiation effectively inhibited tumor growth and prevented lung metastases, leading to a prolonged survival time and improved survival rate. In addition, the designed multitasking MnFe2O4 NPs showed as a good contrast agent for magnetic resonance (MR) imaging to detect orthotopic breast tumor in vivo. Our work provides a novel strategy for combined PTT and improved immunotherapy in the treatment of breast and other metastatic cancers.

Metastases are the cause of more than 90 percent of cancer-related deaths. Current treatment methods, including chemotherapy, radiation, and surgery, fail to target the metastases effectively. One potential treatment for metastatic cancer is laser immunotherapy (LIT). LIT combines the use of a photothermal laser with an immunoadjuvant, Glycated Chitosan (GC). GC combined with single-walled carbon nanotubes (SWNTs) has proven to be a viable alternative to traditional cancer treatment methods, when under irradiation of laser with appropriate wavelength. In this study, the effects of low dose and high dose laser irradiation on metastatic pancreatic cancer cell migration were observed. It was found that low dose irradiation increased the migration rate, but the high dose irradiation significantly decreased the migration rate of the cancer cells. When using LIT, the goal is to kill tumor cells and to prompt the correct immune response. If the tumor were irradiated with a low dose, it would promote metastasis. If the dose of irradiation were too high, it would destroy the entire tumor and the immune response would not recognize the tumor. Therefore, the laser dose plays an important role in LIT, particularly when using SWNT as light absorbing agent. Our results from this study will delineate the optimal laser irradiation dose for destroying tumor cells and at the same time preserve and release tumor antigens as a precursor of antitumor immune response.

We report the synthesis and characterization of arginine-glycine-aspartic acid (RGD) peptide-targeted polyethylenimine (PEI)-entrapped gold nanoparticles (RGD-Au PENPs) for targeted CT imaging of hepatic carcinomas in situ. In this work, PEI sequentially modified with polyethylene glycol (PEG), and RGD linked-PEG was used as a nanoplatform to prepare AuNPs, followed by complete acetylation of PEI surface amines. We showed that the designed RGD-Au PENPs were colloidally stable and biocompatible in the given concentration range, and could be specifically taken up by αvβ3 integrin-overexpressing liver cancer cells in vitro. Furthermore, in vivo CT imaging results revealed that the particles displayed a great contrast enhancement of hepatic carcinomas region, and could target to hepatic carcinomas region in situ. With the proven biodistribution and histological examinations in vivo, the synthesized RGD-Au PENPs show a great formulation to be used as a contrast agent for targeted CT imaging of different αvβ3 integrin receptoroverexpressing tumors.

Temperature increase in tumour tissue during photothermal therapy (PTT) is a significant factor in determining the outcomes of the treatment. Therefore, controlling and optimising temperature distribution in target tissue is crucial for PTT. In this study, we developed a unique ex vivo device to study the temperature distribution during PTT to be used as a guide for the desired photothermal effects for cancer treatment.Bovine liver tissue buried inside agarose gel served as a phantom tumour surrounded by normal tissue. A thermostatic incubator was used to simulate tissue environment in live animals. The temperature distributions were measured by thermocouples with needle probes at different locations inside the target tissue, during laser irradiation using an 805-nm laser.The results obtained using the ex vivo device were verified by comparing the tissue temperature directly measured in animal tumours irradiated under the same conditions. With this model, the spatial distribution of temperature in target tissue can be monitored in real time. A two-dimensional temperature distribution in target tissue allows us to establish the correlations among laser parameters, temperature distribution and tumour size. In addition, the optimal temperature range for tumour destruction and immunological stimulation was determined using metastatic rat mammary tumour model.The device and method developed in this study can provide guidance for choosing the appropriate treatment parameters for optimal photothermal effects, particularly when combined with immunotherapy, for cancer treatment.

We have recently developed Laser Immunotherapy (LIT), a targeted cancer treatment modality using synergistic application of near-infrared laser irradiation and in situ immunological stimulation. This study further investigates the principles underlying the immune response to LIT treatment by studying immunological impact of the laser photothermal effect in vivo, in vitro, and ex vivo. Tumor cells were stressed in vitro, and samples were collected to analyze protein expression with a Western Blot. Additionally, a tumor model was designed using bovine liver tissue suspended in agarose gel which was treated using laser interstitially and monitored with both proton-resonance frequency shift MR thermometry and thermocouples. From the bovine liver tumor model, we were able to develop the correlation between tissue temperature elevation and laser power and distance from the fiber tip. Similar data was collected by monitoring the temperature of a metastatic mammary tumor in a rat during laser irradiation. Ultimately, these results show that the laser irradiation of LIT leads to clear immunological effects for an effective combination therapy to treat metastatic cancers.

Pancreatic cancer is an extremely malignant disease with high mortality rate. Currently there is no effective therapeutic strategy for highly metastatic pancreatic cancers. Laser immunotherapy (LIT) is a combination therapeutic approach of targeted phototherapy and immunotherapy, which could destroy treated primary tumors with elimination of untreated metastases. LIT affords a remarkable efficacy in suppressing tumor growth in pancreatic tumors in mice, and results in complete tumor regression in many cases. LIT could synergize targeted phototherapy and immunological effects of immunoadjuvant, which represent a promising treatment modality to induce systemic antitumor response through a local intervention, paving the way for the treatment of highly metastatic pancreatic cancers.

Immunologically oriented therapy (immunotherapy) has arguably proved to be the most effective method for treating advanced melanoma, the prototypical chemotherapy-resistant solid tumor. The efficacy and benefit of immunotherapy for other tumors, including those that are at least partly responsive to chemotherapy, is less well established. Breast cancer, one of the most common of the solid tumors in humans, is partially responsive to traditional chemotherapy. We believe that breast cancer patients, like melanoma patients, will benefit from the application of immunotherapy techniques. Here we review the different forms of laser immunotherapy (LIT), a key type of immunologically oriented therapy, discuss its use in melanoma and in breast cancer, and discuss its potentially pivotal role in the immunotherapy armamentarium.

Laser Immunotherapy (LIT) is an innovative cancer treatment modality that is specifically targeted towards treating late-stage, metastatic cancer. This treatment modality utilizes laser irradiation in combination with active immune system stimulation to induce a systemic anti-tumor immune response against metastatic cancer. Nanoparticles have recently been utilized to support and increase the photothermal effect of the laser irradiation by absorbing the light energy produced from the laser and converting that energy into thermal energy. In the past, single-walled carbon nanotubes (SWNTs) have been the main choice in nanotechnology, however, recent studies have shown that gold nanorods (AuNRs) are a prospective alternative that may produce photothermal effects similar to SWNTs. Due to the precedence of gold biomaterials currently having approval for use in various treatments for humans, AuNRs are regarded to be a safer option than SWNTs. The goal of this study is to precisely compare any differences in photothermal effects between AuNRs and SWNTs. Both types of nanoparticles were irradiated with the same wavelength of near-infrared light to ascertain the photothermal effects in gel phantom tumor models, aqueous solutions, and metastatic cancer cell cultures. We discerned from the results that the AuNRs could be equally or more effective than SWNTs in absorbing the light energy from the laser and converting it into thermal energy. In both solution and gel studies, AuNRs were shown to be more efficient than SWNTs in creating thermal energy, while in cell studies, no definitive differences between AuNRs and SWNTs were observed. The cytotoxicity of both nanoparticles needs further assessment in future studies. Given these results, AuNRs are comparable to SWNTs, even superior in certain aspects. This advances the opportunity to use AuNRs as replacements for SWNTs in LIT treatments. The results from this study will contribute to any subsequent studies in the development of this cancer modality using photothermal therapy enhanced by nanoparticles.

Non-invasive laser immunotherapy (NLIT) is a viable alternative to traditional cancer treatment because it combines the photothermal and immunological effects of non-invasive laser irradiation and single-walled carbon nanotubes (SWNT) with an immunoadjuvant, glycated chitosan (GC). This combination forms SWNT-GC, a photosensitive immunoadjuvant, which creates a tumor-specific immunity that targets both the primary tumor and any metastasis. It is known that NLIT induces anti-tumor as well as anti-metastatic immune responses, but its immunological mechanism is not clear. The objective of this study is to clarify the role of SWNT-GC in cancer cell migration. Panc02 (non-metastatic) and Panc02-H7 (metastatic) pancreatic cancer cells were used in two-dimensional elastomer plug assays to observe the restriction of cell migration induced by SWNT, GC, and SWNT-GC individually. To replicate a three-dimensional in vivo study, a similar assay was repeated using embedded collagen lattices. Both the 2D and the 3D studies confirmed previous results indicating that GC inhibits cancer cell motility. The 2D and 3D studies also showed that SWNT-GC inhibited the migration of cancer cells, but a discrepancy was observed regarding the effect of SWNT alone. The 2D model concluded that SWNT inhibited migration while the 3D model determined that SWNT promoted migration. The results of this study will guide future work to determine the mechanism behind NLIT, including how metastases are eradicated and how the tumor specific immunity is created.

To evaluate the efficacy and safety of photothermal with dinitrophenyl hapten (DNP) for patients with malignant melanoma (MM), Patients with pathology confirmed stage III or IV MM were enrolled. Seventy-two patients were randomized into two groups, DNP alone group (n=36) and DNP plus photothermal therapy group (n=36). The results showed that the patients in the combination treatment group had longer median progression-free survival time (19.0m vs. 12.0m, p=0.007). No severe adverse events were observed in both groups. Thus, the combination of photothermal therapy and DNP maybe a new therapeutic strategy for patients with advanced MM.

Integrin α v β 3 is a heaterodimeric transmembrane receptor, overexpressed in some types of tumor cells such as glioblastoma U87-MG cells. Integrin α v β 3 , as a tumor biomark, is widely used in cancer diagnosis and therapy. In this work we propose an active targeting nanocarrier system based on nano-graphene oxide (NGO-mAb-FITC) for imaging and photothermal therapy (PTT), in which glioblastoma U87-MG cells are used as the model of tumor therapy. The nanoprobes efficiently target U87-MG cells (integrin α v β 3 -positive), with minimal influence on MCF-7 cells (integrin α v β 3 -negative). These NGO-mAb-FITC nanoprobes are then internalized into the α v β 3 -positive tumor cells. Under 808 nm light irradiation, cells can be ablated by hyperthermia-induced apoptosis. The results indicate that the graphene oxide, a potential photothermal transduction nanoprobe, may potentially serve as a novel probe for cancer targeted imaging and therapy.

We constructed a multifunction nano system SWNT-GC and investigated the synergize photothermal and immunological effects. Here, we improve the SWNT-GC nano system and design a new synergistic nano-particle, both have the photothermal effects and immunological effects. We investigate the therapeutic effects and detect the immune response with metastatic mouse tumor models. We also study the therapeutic mechanism after treatment in vitro and in vivo. With the enhancement of nano-materials on photothermal effects, laser treatment could destroy primary tumor and protect normal tissue with low dose laser irradiation. With the immunological effects of nano-materials, the treatment could trigger specific antitumor immune response, to eliminate the metastasis tumor. It is providing a promising treatment modality for the metastatic cancers.

Laser immunotherapy (LIT) uses laser irradiation and immunological stimulation to target all types of metastases and creates a long-term tumor resistance. Glycated chitosan (GC) is the immunological stimulant used in LIT. Interestingly, GC can act as a surfactant for single-walled carbon nanotubes (SWNTs) to immunologically modify SWNTs. SWNT-GC retains the optical properties of SWNTs and the immunological functions of GC to help increase the selectivity of the laser and create a more optimal immune response. One essential aspect of understanding this immune response is knowing how laser irradiation affects cancer cells’ ability to metastasize. In this experiment, a cell migration assay was performed. A 2mm circular elastomer plugs were placed at the bottom of multi-well dishes. Pre-cancerous keratinocytes, different tumor cells, and fibroblasts were then plated separately in treated wells. Once the cells reached 100% confluence, they were irradiated by either a 980nm or 805nm wavelength laser. The goal was to determine the effects of laser irradiation and immunological stimulation on cancer cell migration in vitro, paying the way to understand the mechanism of LIT in treating metastatic tumors in cancer patients.

Laser Immunotherapy is a novel cancer treatment modality that has seen much success in treating many different types of cancer, both in animal studies and in clinical trials. The treatment consists of the synergistic interaction between photothermal laser irradiation and the local injection of an immunoadjuvant. As a result of the therapy, the host immune system launches a systemic antitumor response. The photothermal effect induced by the laser irradiation has multiple effects at different temperature elevations which are all required for optimal response. Therefore, determining the temperature distribution in the target tumor during the laser irradiation in laser immunotherapy is crucial to facilitate the treatment of cancers. To investigate the temperature distribution in the target tumor, female Wistar Furth rats were injected with metastatic mammary tumor cells and, upon sufficient tumor growth, underwent laser irradiation and were monitored using thermocouples connected to locally-inserted needle probes and infrared thermography. From the study, we determined that the maximum central tumor temperature was higher for tumors of less volume. Additionally, we determined that the temperature near the edge of the tumor as measured with a thermocouple had a strong correlation with the maximum temperature value in the infrared camera measurement.

In vitro photoacoustic therapy using modified single-walled carbon nanotubes (SWNTs) as "bomb" agents is a newly reported approach for cancer. Herein, a mitochondria-targeting photoacoustic modality using unmodified SWNTs and its in vitro and in vivo antitumor effect are reported. Unmodified SWNTs can be taken up into cancer cells due to a higher mitochondrial transmembrane potential in cancerous cells than normal cells. Under the irradiation of a 1064 nm pulse laser, 79.4% of cancer cells with intracellular SWNTs die within 20 s, while 82.3% of normal cells without SWNTs remain alive. This modality kills cancer cells mainly by triggering cell apoptosis that initiates from mitochondrial damage, through the depolarization of mitochondria and the subsequent release of cytochrome c after photoacoustic therapy. It is very effective in suppressing tumor growth by selectively destroying tumor tissue without causing epidermis injury. Taken together, these discoveries provide a new method using mitochondria-localized SWNTs as photoacoustic transducers for cancer treatment.

Pancreatic cancer is a malignant tumor model with high mortality. Many patients are ineligible for surgical resection once diagnosed; therefore, it is important to explore more safe and effective treatment options. This study was designed to determine the therapeutic effect of reduced graphene oxide combined with the near-infrared laser in animal pancreatic cancer. The results showed that reduced graphene oxide has strong light absorption ability between 600 and 1100 nm detected by spectrophotometer. Experimental results of different concentrations of reduced graphene oxide solution under 980-nm laser irradiation at different powers showed that the enhancement of the photothermal conversion effect of reduced graphene oxide depends on reduced graphene oxide concentration and light dose. In vivo experiments showed that higher laser dose (0.75 W/cm2) combined with higher reduced graphene oxide concentration (2 mg/kg) can achieve higher treatment temperature and slower tumor growth. These results suggest that reduced graphene oxide combined with the 980-nm laser in the treatment of mouse pancreatic cancer can get an ideal thermal killing effect, with the clinical potential of pancreatic cancer treatment.

Dendritic cell (DC) based vaccine has emerged as a promising immunotherapy for cancers. However, most DC vaccines so far have only achieved limited success in cancer treatment. Photodynamic therapy (PDT), an established cancer treatment strategy, can cause immunogenic apoptosis to induce an effective antitumor immune response. In this study, we developed a DC-based cancer vaccine using immunogenic apoptotic tumor cells induced by 5-aminolevulinic acid (ALA) mediated PDT. The maturation of DCs induced by PDT-treated apoptotic cells was evaluated. The anti-tumor immunity of ALA-PDT-DC vaccine was tested with mouse model. We observed the maturations of DCs potentiated by ALA-PDT treated tumor cells, including phenotypic maturation (upregulation of surface expression of MHC-II, DC80, and CD86), and functional maturation (enhanced capability to secret INF-Υ and IL-12). ALA-PDT-DC vaccine mediated by apoptotic cells provided protection against tumor in mice, far stronger than that of DC vaccine obtained from freeze/thaw treated tumor cells. Our results indicate that immunogenic apoptotic tumor cells can be more effective in enhancing DC-based cancer vaccine, which could improve the clinical application of PDT- DC vaccines.

In our previous work, we constructed a multifunctional nano system, using single-walled carbon nanotube (SWNT) and glycated chitosan (GC), which can synergize photothermal and immunological effects. To further confirm the therapy efficacy, with a metastatic mouse mammary tumor model (4T1), we investigate the therapy effects and immune response induced by SWNT-GC, under laser irradiation. Laser+SWNT-GC treatment not only suppressed the prime tumor, but also induced antitumor immune response. It could be developed into a promising treatment modality for the metastatic breast cancer.

Laser immunotherapy (LIT) is an innovative cancer modality that uses laser irradiation and immunological stimulation to treat late-stage, metastatic cancers. LIT can be performed through either interstitial or non-invasive laser irradiation. Although LIT is still in development, recent clinical trials have shown that it can be used to successfully treat patients with late-stage breast cancer and melanoma. The development of LIT has been focused on creating an optimal immune response created by irradiating the tumor. One important factor that could enhance the immune response is the duration of laser irradiation. Irradiating the tumor for a shorter or longer amount of time could weaken the immune response created by LIT. Another factor that could weaken this immune response is the proliferation of regulatory T cells (TRegs) in response to the laser irradiation. However, low dose cyclophosphamide (CY) can help suppress the proliferation of TRegs and help create a more optimal immune response. An additional factor that could weaken the effectiveness of LIT is the selectivity of the laser. If LIT is performed non-invasively, then deeply embedded tumors and highly pigmented skin could cause an uneven temperature distribution inside the tumor. To solve this problem, an immunologically modified carbon nanotube system was created by using an immunoadjuvant known as glycated chitosan (GC) as a surfactant for single-walled carbon nanotubes (SWNTs) to immunologically modify SWNTs. SWNT-GC retains the optical properties of SWNTs and the immunological functions of GC to help increase the selectivity of the laser and create a more optimal immune response. In this preliminary study, tumor-bearing rats were treated with LIT either interstitially by an 805-nm laser with GC and low-dose CY, or non-invasively by a 980-nm laser with SWNT-GC. The goal was to observe the effects of CY on the immune response induced by LIT and to also determine the effect of irradiation duration for interstitial and noninvasive LIT.

Laser immunotherapy (LIT), a novel technique with a local intervention to induce systemic antitumor effects, was developed to treat metastatic cancers. The pre-clinical studies of LIT have shown its unique characteristics in generating a specific antitumor immunity in treating metastatic tumors in rats and mice. For late-stage, metastatic breast cancer patients, who were considered to be out of other available treatment options, we conducted a small Phase II clinical trial using LIT starting in 2009 in Lima, Peru. This Phase II study was closed in December of 2012, as acknowldged by the Ministry of Health (MOH) of Peur letter 438-2014-OGITT/INS dated March 5th, 2014. Ten patients were enrolled and received LIT in one or multiple 4-week treatment cycles. At the study closing date, four patients were alive and two of them remained cancer free. Here, following the successful conclusion of our Phase II study, we report the clinical effects of LIT on metastatic breast cancer patients. Specifically, we present the overall status of all the patients three years after the treatment and also the outcomes of two long-term surviving patients.

In our previous work, we constructed a multifunction nano system SWNT-GC, which can synergize photothermal and immunological effects. To further improve the application of this system, we study the cytotoxicity of SWNT-GC and investigate the effects on malignant tumor therapy. Here, we selected the optimal concentration of GC and SWNTs for the stable SWNT-GC construction. No cytotoxicity was observed under the dose used in the experiments. Using mouse melanoma tumor model, Laser+SWNT-GC treatment resulted in a significant mice survival rate, there were no long-term survivors under other treatment. It is providing a promising treatment modality for the malignancy.

It has been known for a long time that microglial activation plays an important role in the pathology of neurodegenerative diseases. Once activated, they have macrophage-like capabilities, which can be detrimental by producing proinflammatory and neurotoxic factors including cytokines, reactive oxygen species (ROS) and nitric oxide that directly or indirectly cause neurodegeneration. Therefore, the regulation of microglial-induced neuroinflammation is considered a useful strategy in searching for neuroprotective treatments. In this study, our results showed that low power laser irradiation (LPLI) (20 J/cm 2 ) could suppress microglial-induced neuroinflammation in LPS-activated microglia. We found that LPLI-mediated neuroprotection was achieved by activating tyrosine kinases Src, which led to MyD88 tyrosine phosphorylation, thus impairing MyD88-dependent proinflammatory signaling cascade. Our research may provide a feasible therapeutic approach to control the progression of neurodegenerative diseases.

T-cell stimulators such as anti-CTLA-4 antibodies enhance immunologic responses to chemotherapy-resistant solid tumors, such as melanoma, advanced breast cancer, ovarian cancer and pancreatic cancer. The efficacy of these new immunotherapy agents can in theory be enhanced substantially by therapies that stimulate new immunologic (T-cell) responses against the tumor. Laser immunotherapy (LIT) with imiquimod and InCVAX are techniques that produce useful responses in patients with advanced melanoma, the prototypical chemotherapy resistant solid tumor. The mechanism of action of these therapies is thought to be immunological, including the development of new T-cell responses. We have therefore been combining LIT using imiquimod and InCVAX treatment with the new T-cell stimulators (ipilimumab) in cases of stage IV melanoma. While still anecdotal, the use of novel combinations of immunologic therapies should provide much improved responses for chemotherapy-resistant solid tumors (such as melanoma) than was previously possible. Newer T-cell stimulating drugs such as the anti-PD-1 antibodies and anti-PD-L1 antibodies will make this general approach to treating chemoresistant advanced tumors even more effective in the future.

While successes of different cancer therapies have been achieved in various degrees a systemic immune response is needed to effectively treat late-stage, metastatic cancers, and to establish long-term tumor resistance in the patients. A novel method for combating metastatic cancers has been developed using immunologically modified carbon nanotubes in conjunction with phototherapy. Glycated chitosan (GC) is a potent immunological adjuvant capable of increasing host immune responses, including antigen presentation by activation of dendritic cells (DCs) and causing T cell proliferation. GC is also an effective surfactant for nanomaterials. By combining single-walled carbon nanotubes (SWNTs) and GC, immunologically modified carbon nanotubes (SWNT-GC) were constructed. The SWNT-GC suspension retains the enhanced light absorption properties in the near infrared (NIR) region and the ability to enter cells, which are characteristic of SWNTs. The SWNT-GC also retains the immunological properties of GC. Cellular SWNT-GC treatments increased macrophage activity, DC activation and T cell proliferation. When cellular SWNT-GC was irradiated with a laser of an appropriate wavelength, these immune activities could be enhanced. The combination of laser irradiation and SWNT-GC induced cellular toxicity in targeted tumor cells, leading to a systemic antitumor response. Immunologically modified carbon nanotubes in conjunction with phototherapy is a novel and promising method to produce a systemic immune response for the treatment of metastatic cancers.

Targeted immunotherapy using dendritic cell (DC) vaccine has been employed for the treatment of solid tumors. Topical 5-aminolevulinic acid mediated photodynamic therapy (ALA-PDT), an established approach for topical cancers, can induce an effective antitumor immune response.We have previously shown that ALA-PDT-induced tumor lysates could considerably enhance antigen-presenting capacity of ex vivo-generated DCs.The current study further demonstrates that ALA-PDT-DC vaccine can induce immune responses against cancers.DC cells pulsed by PDT-treated cutaneous squamous cell carcinoma (cSCC) cells inhibited SCC to a greater extent than tumor lysates treated by PDT alone or DCs pulsed by freeze/thawed treated tumor cells (FT-DC).Immunohistochemistry showed that PDT-DC vaccine could increase the activity of CD4+ and CD8+ T cells in the tumor implantation sites.Flow cytometry assays showed that CD4+ and CD8+ T cells in the spleens of PDT-DC vaccine immunized mice increased significantly.Furthermore, we observed increased amounts of IL-12 and IFN-γ and decreased amounts of IL-10 in the splenocytes and peripheral blood of PDT-DC vaccine immunized mice by ELISA.Taken together, our findings suggest that PDT-DC vaccination is an effective prophylactic therapy for cSCC. Note: This abstract was not presented at the conference. Citation Format: Haiyan Zhang, Guolong Zhang, Zhixia Fan, Xiaojie Wang, Lei Shi, Degang Yang, Cody F. Bahavar, Feifan Zhou, Wei R. Chen, Xiuli Wang. Antitumor effects of improved DC vaccine with ALA-PDT induced immunogenic apoptotic cells for skin squamous cell carcinoma in mice [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A139.

Photonics immunotherapy is a novel cancer treatment strategy that combines local phototherapy and immunotherapy. Phototherapy is a noninvasive or minimally invasive therapeutic strategy for local treatment of cancer, which can destroy tumor cells and release tumor antigens, inducing an in situ antitumor immune response. Immunotherapy, including the use of antibodies, vaccines, immunoadjuvants and cytokines, when combined with phototherapy, could bring a synergistic effect to stimulate a host immune response that effectuates a long-term antitumor immunity. This review will focus on the development of photonics immunotherapy and its systemic antitumor immunological effects.

In the current study, we explore novel phototherapy model for cancer with mitochondria-targeting single-walled carbon nanotubes (SWNTs), which could prove to be a promising selective local treatment modality, while minimizing adverse side effects.

Nanomaterials have recently attracted much attention as efficient transducers for cancer photothermal therapy, based on their intrinsic absorption properties in the near-infrared region. This study explores a novel therapy model with mitochondria-targeting single-walled carbon nanotubes (SWNTs), which act efficiently to convert 980-nm laser energy into heat and selectively destroy the target mitochondria, thereby inducing mitochondrial depolarization, cytochrome c release, and caspase 3 activation. The laser+SWNTs process affords remarkable efficacy in suppressing tumor growth in a breast cancer model, and results in complete tumor regression in some cases. Laser+SWNTs could prove to be a promising selective local treatment modality, while minimizing adverse side effects.

Laser immunotherapy (LIT) has shown its efficacy against late-stage, metastatic cancers, both in pre-clinical studies and clinical pilot trials. However, the possible mechanism of LIT is still not fully understood. In our previous studies, we have shown that LIT induces tumor-specific antibodies that strongly bind to the target tumors. Tumor resistance in cured animals demonstrated long-term immunological effect of LIT. Successful transfer of adoptive immunity using spleen cells from LIT-cured animals indicated a long-term immunological memory of the host system. In clinical trials for the treatment of late-stage melanoma patients and breast cancer patients, the similar long-term, systemic effects have also been observed. To further study the immunological mechanism of LIT, immuno-histochemical analysis of patient tumor samples has performed before and after LIT treatment. Our results showed strong evidence that LIT significantly increases the infiltration of immune cells in the target tumors. Specifically, LIT appeared to drive the infiltrating immune cell populations in the direction of CD4, CD8 and CD68 T-cells. It is possible that activation and enhancement of both humeral and cellular arms of the host immune system are achievable by the treatment of LIT. These special features of LIT have contributed to the success of patient treatment. The underlying mechanism of LIT appears to be an in-situ autologous whole-cell cancer vaccination, using all components of tumors as sources of tumor antigens. Our preliminary mechanistic studies and future in-depth studies will contribute to the understanding and development of LIT as an effective modality for the treatment of late stage cancer patients who are facing severely limited options.

The ideal treatment modality for metastatic cancer would be a local treatment that can destroy primary tumors while inducing an effective systemic anti-tumor response. To this end, we developed laser immunotherapy, combining photothermal laser application with an immunoadjuvant for the treatment of metastatic cancer. Additionally, to enhance the selective photothermal effect, we integrated light-absorbing nanomaterials into this innovative treatment. Specifically, we developed an immunologically modified carbon nanotube combining single-walled carbon nanotubes (SWNTs) with the immunoadjuvant glycated chitosan (GC). To determine the effectiveness of laser irradiation, a series of experiments were performed using two different irradiation durations — 5 and 10 min. Rats were inoculated with DMBA-4 cancer cells, a metastatic cancer cell line. The treatment group of rats receiving laser irradiation for 10 min had a 50% long-term survival rate without residual primary or metastatic tumors. The treatment group of rats receiving laser irradiation for 5 min had no long-term survivors; all rats died with multiple metastases at several distant sites. Therefore, Laser+SWNT–GC treatment with 10 min of laser irradiation proved to be effective at reducing tumor size and inducing long-term anti-tumor immunity.

Microglial activation plays an important role in neurodegenerative diseases. Once activated, they have macrophage-like capabilities, which can be beneficial by phagocytosis and harmful by secretion of neurotoxins. However, the resident microglia always fail to trigger an effective phagocytic response to clear dead cells or Aβ deposits during the progression of neurodegeneration. Therefore, the regulation of microglial phagocytosis is considered a useful strategy in searching for neuroprotective treatments. In this study, our results showed that low-power laser irradiation (LPLI) (20 J/cm2) could enhance microglial phagocytic function in LPS-activated microglia. We found that LPLI-mediated microglial phagocytosis is a Rac-1-dependent actin-based process, that a constitutively activated form of Rac1 (Rac1Q61L) induced a higher level of actin polymerization than cells transfected with wild-type Rac1, whereas a dominant negative form of Rac1 (Rac1T17N) markedly suppressed actin polymerization. In addition, the involvement of Rac1 activation after LPLI treatment was also observed by using a Raichu fluorescence resonance energy transfer (FRET)-based biosensor. We also found that PI3K/Akt pathway was required in the LPLI-induced Rac1 activation. Our research may provide a feasible therapeutic approach to control the progression of neurodegenerative diseases.

While antitumor immunological responses have been mainly associated with necrosis, immune responses associated with apoptosis have been suggested recently. In this study, the relationship between cell death and its interaction with macrophage were studied using Photofrin-PDT induced necrosis and apoptosis.