Immune modulations of the tumor microenvironment in response to phototherapy.

The tumor microenvironment (TME) promotes pro-tumor and anti-inflammatory metabolisms and suppresses the host immune system. It prevents immune cells from fighting against cancer effectively, resulting in limited efficacy of many current cancer treatment modalities. Different therapies aim to overcome the immunosuppressive TME by combining various approaches to synergize their effects for enhanced anti-tumor activity and augmented stimulation of the immune system. Immunotherapy has become a major therapeutic strategy because it unleashes the power of the immune system by activating, enhancing, and directing immune responses to prevent, control, and eliminate cancer. Phototherapy uses light irradiation to induce tumor cell death through photothermal, photochemical, and photo-immunological interactions. Phototherapy induces tumor immunogenic cell death, which is a precursor and enhancer for anti-tumor immunity. However, phototherapy alone has limited effects on long-term and systemic anti-tumor immune responses. Phototherapy can be combined with immunotherapy to improve the tumoricidal effect by killing target tumor cells, enhancing immune cell infiltration in tumors, and rewiring pathways in the TME from anti-inflammatory to pro-inflammatory. Phototherapy-enhanced immunotherapy triggers effective cooperation between innate and adaptive immunities, specifically targeting the tumor cells, whether they are localized or distant. Herein, the successes and limitations of phototherapy combined with other cancer treatment modalities will be discussed. Specifically, we will review the synergistic effects of phototherapy combined with different cancer therapies on tumor elimination and remodeling of the immunosuppressive TME. Overall, phototherapy, in combination with other therapeutic modalities, can establish anti-tumor pro-inflammatory phenotypes in activated tumor-infiltrating T cells and B cells and activate systemic anti-tumor immune responses.

Synergistic interventional photothermal therapy and immunotherapy using an iron oxide nanoplatform for the treatment of pancreatic cancer.

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.

Identification of hepatosensitive region and their neural connections in the hippocampus of rats.

BACKGROUND: Visceral function localisation of the brain is very complex. For many years, people have been actively exploring the neural mechanism regulating visceral and substance metabolism, clarifying the complex relationship between the brain and peripheral nervous system related to the regulation of visceral activity, and analysing its complex neural pathways. The brain is the advanced centre of visceral function regulation. As an advanced centre for substance metabolism and visceral regulation, the hippocampus is crucial for regulating visceral function. The liver is the core organ of material metabolism, and its afferent signals are mainly projected to the nucleus of the solitary tract (NTS) through vagus nerve, and then they are projected to the hypothalamus and limbic system. MATERIALS AND METHODS: We placed a stereotaxic instrument on the head of each rat and performed craniotomy to open a window above the left hippocampus. We used gold-plated tungsten electrodes to monitor hippocampal neuronal discharges. Grounding was achieved using screws and silver wire. We electrically stimulated the liver branch of the vagus nerve and observed changes in hippocampal neuron discharges using a biological method; in this way, we identified hepatosensitive hippocampal region. We injected FluoroGold into this region and related brain areas. After 3 days, the rats were sacrificed and perfused; the hippocampi were fixed, dehydated, frozen, sectioned, and subjected to fluorescence microscopy. RESULTS: Nerve discharge frequency and amplitude significantly increased in the hippocampal CA3 region (AP: -4.9, ML: -5.1, DV: -5.0 mm). After FluoroGold was injected into the left hepatosensitive region in the hippocampus, labelled cells were found in the contralateral hippocampus, ipsilateral piriform cortex (PC), locus coeruleus (LC) and bilateral lateral hypothalamus (LHA); fluorescence in the ipsilateral hypothalamus was stronger than that of the contralateral hypothalamus. FluoroGold was injected into the LHA, PC, and LC; no labelled cells were found in the hippocampal CA3 region or in the control group. CONCLUSIONS: The hippocampal CA3 area of rats may contain a hepatosensitive region that plays important roles in the regulation of liver and other organ function. This region may receive input from the LHA, PC, and LC.

Transcriptomic analysis of mechanism of melanoma cell death induced by photothermal therapy.

Melanoma is a malignancy with poor prognosis. Its incidence rate has been on the rise and it poses high health and economic challenges to different populations. Photothermal therapy (PTT) served as an effective local therapy in treating various tumors, particularly cutaneous carcinoma like melanoma. To fully understand the mechanisms of tumor cell death induced by PTT, we investigated gene expression and immune cells compositions of B16-F10 tumors after PTT treatment. A total of 256 differentially expressed genes (DEGs) were identified, with 215 being downregulated and 41 upregulated by PTT. Functional annotation showed that most DEGs involved in immune response and inflammatory response. Immune cells compositions inference revealed changes in many immune cells including regulatory T cells, M2 macrophage and B cells after PTT treatment. Our results help delineate the mechanism of cell death at the transcriptional level triggered by non-invasive PTT treatment of melanoma without exogenous light absorbing agents.

Cancer photo-immunotherapy: from bench to bedside.

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.

Photo-activated chemo-immunotherapy for metastatic cancer using a synergistic graphene nanosystem.

We developed a novel treatment strategy for metastatic cancer by synergizing photothermal therapy (PTT), chemotherapy, and immunotherapy through a nanosystem to trigger host antitumor immunity. The nanosystem was constructed by loading mitoxantrone (MTX), a chemotherapeutic agent, and SB-431542 (SB), a transforming growth factor beta (TGF-ß) inhibitor, onto reduced graphene oxide (rGO). Intratumoral administration of rGO/MTX/SB, followed by non-invasive irradiation of a near-infrared laser, destroyed local primary tumors and inhibited distant metastases in 4T1 mouse mammary tumor model, which is poorly immunogenic and highly metastatic. After treatment, 70% of the tumor-bearing mice became long-term survivors and developed a tumor type-specific immunity to resist rechallenged tumor cells. We found that rGO-based PTT provided an immunogenic antigen source, forming in situ vaccination with rGO as an immune-adjuvant. The use of SB changed the tumor microenvironment and improved the therapeutic effect of MTX-generated chemotherapy and rGO-based PTT. The immunological functions of MTX, SB, and rGO acted synergistically to induce an effective tumor vaccination, as evidenced by the increased infiltration of tumor-specific cytotoxic CD8+ T lymphocytes and decreased infiltration of regulatory T cells (Tregs) in distal tumors. Collectively, we demonstrated that rGO/MTX/SB combined with laser irradiation provided a synergistic chemo-immuno-photothermal effect against tumors by in situ vaccination and inhibition of immunosuppressive microenvironment. This unique combination embodies a promising approach to treat metastatic cancers by inducing a systemic antitumor response through a local intervention.

Biodegradable pH-responsive amorphous calcium carbonate nanoparticles as immunoadjuvants for multimodal imaging and enhanced photoimmunotherapy.

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.

Neutrophil infiltration and whole-cell vaccine elicited by N-dihydrogalactochitosan combined with NIR phototherapy to enhance antitumor immune response and T cell immune memory.

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.

N-dihydrogalactochitosan-supported tumor control by photothermal therapy and photothermal therapy-generated vaccine.

Photothermal therapy (PTT) is recently clinically established cancer therapy that uses near-infrared light for thermal ablation of solid tumors. The biopolymer N-dihydrogalactochitosan (GC) was shown in multiple reports to act as a very effective adjunct to tumor PTT. In the present study, mouse tumor model SCCVII (squamous cell carcinoma) was used with two protocols, in situ tumor PTT and therapeutic PTT vaccine for tumors, for investigating the effects of GC. The results reveal that GC can potentiate tumoricidal action of PTT through both direct and indirect mechanisms. In addition to previously known capacity of GC for activating immune effector cells, the indirect means is shown to include reducing the populations of immunoregulatory T cells (Tregs) in PTT-treated tumors. Testing the effects of GC on PTT-treated SCCVII tumor cells in vitro uncovered the existence of a direct mechanism evident by reduced colony survival of these cells. Fluorescence microscopy demonstrated increased binding of fluorescein-labeled GC to PTT-treated compared to untreated SCCVII cells that can be blocked by pre-exposure to annexin V. The results of additional in vitro testing with specific inhibitors demonstrate that these direct mechanisms do not involve the engagement of death surface receptors that trigger extrinsic apoptosis pathway signaling but may be linked to pro-survival activity of caspase-1. Based on the latter, it can be suggested that GC-promoted killing of PTT-treated cells stems from interference of GC bound to damaged membrane components with the repair of these structures that consequently hinders cell survival.

PEGylated reduced-graphene oxide hybridized with Fe3O4 nanoparticles for cancer photothermal-immunotherapy.

Photoimmunotherapy has attracted much attention recently for the treatment of metastatic tumors. The development of smart nanocomposites for imaging-guided therapies is 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 Fe3O4 nanoparticles (FNPs) with reduced-graphene oxide (rGO) through electrostatic interaction, modified by PEG-NH2 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 the 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 could also 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.

Concurrent photothermal therapy and photodynamic therapy for cutaneous squamous cell carcinoma by gold nanoclusters under a single NIR laser irradiation.

Phototherapy, particularly photothermal therapy (PTT) and photodynamic therapy (PDT), has become a promising therapeutic technique for the treatment of skin cancers because of its minial invasiveness, high efficacy, and low side effects. Nevertheless, single modality therapy, either PTT or PDT, has limited clinical effectiveness in treating skin cancers. Thus, combined applications of PTT and PDT have been frequently reported; however, PTT and PDT often require their respective photoagents and excitation light sources, resulting in challenges in clinical transformation. In this study, to address these issues, we report the use of biocompatible gold nanoclusters Au25(Capt)18 for the concurrent PTT and PDT treatment of cutaneous squamous cell carcinoma (cSCC) using an 808 nm near-infrared (NIR) laser. Utilizing their high light-thermal conversion efficiency, potent generation of singlet oxygen, and strong photothermal stability, Au25(Capt)18 nanoclusters potentiated a significant proliferation suppression of cSCC XL50 cells in vitro and the inhibition of cSCC tumors on SKH-1 mice in vivo. In particular, under 808 nm light irradiation, the tumor-cell-killing contributions of PTT and PDT were estimated to be 28.86% and 71.14%, respectively, by using an ROS scavenger to quench the PDT effect. Tumor-infiltrating CD4+ T and CD8+ T cells were observed after one course of concurrent PTT and PDT. Preliminary toxicity studies indicated low adverse effects of the Au25(Capt)18 nanoclusters. Through this study, we report the use of a simple nanostructure for simultaneous PTT and PDT applications to effectively kill cSCC and to induce anti-tumor immune responses. Our study could lead to the development of effective photoagents for current, synergistic applications of different phototherapies with targeted immunological responses for the treatment of cancers.

NIR-Triggered Phototherapy and Immunotherapy via an Antigen-Capturing Nanoplatform for Metastatic Cancer Treatment.

Combined phototherapy and immunotherapy demonstrates strong potential in the treatment of metastatic cancers. An upconversion nanoparticle (UCNP) based antigen-capturing nanoplatform is designed to synergize phototherapies and immunotherapy. In particular, this nanoplatform is constructed via self-assembly of DSPE-PEG-maleimide and indocyanine green (ICG) onto UCNPs, followed by loading of the photosensitizer rose bengal (RB). ICG significantly enhances the RB-based photodynamic therapy efficiency of UCNP/ICG/RB-mal upon activation by a near-infrared (NIR) laser, simultaneously achieving selective photothermal therapy. Most importantly, tumor-derived protein antigens, arising from phototherapy-treated tumor cells, can be captured and retained in situ, due to the functionality of maleimide, which further enhance the tumor antigen uptake and presentation by antigen-presenting cells. The synergized photothermal, photodynamic, and immunological effects using light-activated UCNP/ICG/RB-mal induces a tumor-specific immune response. In the experiments, intratumoral administration of UCNP/ICG/RB-mal, followed by noninvasive irradiation with an NIR laser, destroys primary tumors and inhibits untreated distant tumors, using a poorly immunogenic, highly metastatic 4T1 mammary tumor model. With the simultaneous use of anti-CTLA-4, about 84% of the treated tumor-bearing mice achieve long-term survival and 34% of mice develop tumor-specific immunity. Overall, this antigen-capturing nanoplatform provides a promising approach for the treatment of metastatic cancers.

Phototherapy using immunologically modified carbon nanotubes to potentiate checkpoint blockade for metastatic breast cancer.

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.

Nanotechnology-based photoimmunological therapies for cancer.

Phototherapy is a non-invasive or minimally invasive therapeutic strategy. Immunotherapy uses different immunological approaches, such as antibodies, vaccines, immunoadjuvants, and cytokines to stimulate the host immune system to fight against diseases. In cancer treatment, phototherapy not only destroys tumor cells, but also induces immunogenic tumor cell death to initiate a systemic anti-tumor immune response. When combined with immunotherapy, the effectiveness of phototherapy can be enhanced. Because of their special physical, chemical, and sometimes immunological properties, nanomaterials have also been used to enhance phototherapy. In this article, we review the recent progress in nanotechnology-based phototherapy, including nano-photothermal therapy, nano-photochemical therapy, and nano-photoimmunological therapy in cancer treatment. Specifically, we focus on the immunological responses induced by nano-phototherapies.

Photothermal therapy enhanced the effectiveness of imiquimod against refractory cutaneous warts through boosting immune responses.

Refractory cutaneous warts are difficult to eliminate. In situ photo-immunotherapy (ISPI) is an innovative treatment concept combining local photothermal therapy (PTT) and topical immunotherapy using imiquimod. To compare the efficacy of ISPI vs topical imiquimod alone, a prospective randomized controlled trial was performed with patients suffering from refractory cutaneous warts. In both groups, approximately 50% of the skin surface containing warts was treated for 6 weeks. On the basis of topical imiquimod, ISPI includes an additional 808 nm laser irradiation. Treatment response, temperatures during irradiation and histopathologic examination were evaluated. The complete response rate in the ISPI-group (22/36, 61.1%) was significantly higher than in the imiquimod alone group (11/34, 32.4%). In the ISPI-group, the mean maximum temperature was 44.5 ± 5.1°C, and obvious lymphocytic infiltration was found in the perivasculature of the dermis. There was no recurrence or worsening in both groups during the 12-month follow-up. No obvious adverse reaction was observed. This study demonstrates that ISPI can be used as an effective and safe treatment modality for refractory cutaneous warts.

Monitoring tissue temperature during photothermal therapy for cancer.

Phototherapies offer promising alternatives to traditional cancer therapies. Phototherapies mainly rely on manipulation of target tissue through photothermal, photochemical, or photomechanical interactions. Combining phototherapy with immunotherapy has the benefit of eliciting a systemic immune response. Specifically, photothermal therapy (PTT) has been shown to induce apoptosis and necrosis in cancer cells, releasing tumor associated antigenic peptides while sparing healthy host cells, through temperature increase in targeted tissue. However, the tissue temperature must be monitored and controlled to minimize adverse thermal effects on normal tissue and to avoid the destruction of tumor-specific antigens, in order to achieve the desired therapeutic effects of PTT. Techniques for monitoring PTT have evolved from post-treatment quantification methods like enzyme linked immunosorbent assay, western blot analysis, and flow cytometry to modern methods capable of real-time monitoring, such as magnetic resonance thermometry, computed tomography, and photoacoustic imaging. Monitoring methods are largely chosen based on the type of light delivery to the target tissue. Interstitial methods of thermometry, such as thermocouples and fiber-optic sensors, are able to monitor temperature of the local tumor environment. However, these methods can be challenging if the phototherapy itself is interstitially administered. Increasingly, non-invasive therapies call for non-invasive monitoring, which can be achieved through magnetic resonance thermometry, computed tomography, and photoacoustic imaging techniques. The purpose of this review is to introduce the feasible methods used to monitor tissue temperature during PTT. The descriptions of different techniques and the measurement examples can help the researchers and practitioners when using therapeutic PTT.

BSA-bioinspired gold nanorods loaded with immunoadjuvant for the treatment of melanoma by combined photothermal therapy and immunotherapy.

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.

Local Phototherapy Synergizes with Immunoadjuvant for Treatment of Pancreatic Cancer through Induced Immunogenic Tumor Vaccine.

Purpose: To develop a synergistic combination therapy for advanced pancreatic cancer, using local phototherapy and immunotherapy, and to determine the efficacy and mechanism of the novel combination therapy using a highly metastatic pancreatic tumor model in mice.Experimental Design: Mice bearing Panc02-H7 pancreatic tumors (both subcutaneous and orthotopic) were treated with noninvasive or interventional photothermal therapy, followed by local application of an immunoadjuvant. Tumor growth and animal survival were assessed. Immune cell populations within spleen and tumors were evaluated by FACS and IHC, and cytokine levels were determined by ELISA.Results: Up to 75% of mice bearing subcutaneous tumors treated with combination therapy had complete tumor regression. Local photothermal therapy exposed/released damage-associated molecular patterns, which initiated an immunogenic tumor cell death, resulting in infiltration of antigen-presenting cells and Th1 immunity. Concomitant application of immunoadjuvant amplified Th1 immunity, especially the tumor-specific cytotoxic T lymphocyte response, with increased quantity and quality of T cells. Combination therapy also induced tumor-specific immune memory, as demonstrated by resistance to tumor rechallenge and production of memory T cells. For the treatment of orthotopic tumor, the combination therapy significantly reduced the primary tumors and metastases, and prolonged the animal survival time.Conclusions: This study indicated that combination of local phototherapy and immunotherapy induced a systemic immunity against established tumors and metastases in an aggressive, preclinical pancreatic tumor model, leading to a potential clinical method for patients with advanced pancreatic cancer. Clin Cancer Res; 24(21); 5335-46. ©2018 AACR.

A novel cosmetic and clinically practicable laser immunotherapy for facial verruca plana: Intense pulsed light combined with BCG-PSN.

BACKGROUND: There is no standard method to remove facial verruca plana and achieve better cosmetic effects. The present study is the first study to use intense pulsed light (IPL) as photothermal therapy (PTT) combined with intra-gluteal injection of bacillus calmette-guerin polysaccharide nucleic acid (BCG-PSN), which function as immunotherapy, contracting a new type of clinically available laser immunotherapy (LIT) for the treatment of facial verruca plana. The aim of this study was to evaluate the efficacy, cosmetic outcome, and adverse reactions of IPL combined with BCG-PSN for facial verruca plana. METHODS: Twenty-three patients with facial verruca plana were treated with IPL (560-nm filter, 15-17 J/cm2) and all patients were given intra-gluteal injections of BCG-PSN twice a week for 8 weeks combined with IPL once a month in two times. The clinical responses, recurrences, adverse reactions, and rejuvenation outcomes were evaluated. RESULTS: A complete and excellent response was noted in 17 patients (74%). Of the 676 treated warts, 548 were eradicated and the overall clearance rate was 81%. No patient relapsed during the 20-week follow-up. No obvious adverse reactions was observed. Almost all patients showed an improvement in skin texture after IPL treatment CONCLUSION: We conclude that a novel LIT based on BCG-PSN and IPL for the treatment of facial verruca plana proved to be a well-tolerated and effective treatment modality. This novel LIT can clear skin lesions and achieve a very good cosmetic effect.

Laser immunotherapy for cutaneous squamous cell carcinoma with optimal thermal effects to enhance tumour immunogenicity.

BACKGROUND: Laser immunotherapy is a new anti-cancer therapy combining photothermal therapy and immunostimulation. It can eliminate the tumours by damaging tumour cells directly and promoting the release of damage-associated molecular patterns (DAMPs) to enhance tumour immunogenicity. The aim of this study was to investigate the thermal effects of laser immunotherapy and to evaluate the effectiveness and safety of laser immunotherapy for cutaneous squamous cell carcinoma (cSCC). METHODS: The cell viability and the DAMPs productions of heat-treated cSCC A431 cells in different temperatures were investigated. Laser immunotherapy with the optimal thermal effect for DAMPs production was performed on SKH-1 mice bearing ultraviolet-induced cSCC and a patient suffering from a large refractory cSCC. RESULTS: The temperature in the range of 45-50 °C killing half of A431 cells had an optimal thermal effect for the productions of DAMPs. The thermal effect could be further enhanced by local application of imiquimod, an immunoadjuvant. Laser immunotherapy eliminated most tumours and improved the survival rate of the ultraviolet-induced cSCC-bearing SKH-1 mice (p < 0.05). The patient with cSCC treated by laser immunotherapy experienced a significant tumour reduction after laser immunotherapy increased the amounts of infiltrating lymphocytes in the tumour. No obviously adverse effect was observed in the mice experiment or in the clinical application. CONCLUSIONS: Our results strongly indicate that laser immunotherapy with optimal thermal effects is an effective and safe treatment modality for cSCC.