The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Leaf Huang - One of the best experts on this subject based on the ideXlab platform.
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remodeling the fibrotic tumor microenvironment of Desmoplastic Melanoma to facilitate vaccine immunotherapy
Nanoscale, 2020Co-Authors: Hongda Zhu, Qi Liu, Lei Miao, Sara Musetti, Meirong Huo, Leaf HuangAbstract:Highly fibrotic and collagen-rich properties in Desmoplastic Melanoma (DM) result in an immune-suppressive fibrotic tumor microenvironment (TME) that resists clinical therapies. The different clinical and pathological properties, as compared to conventional Melanoma, lead to delayed diagnosis and it is difficult to deliver drugs effectively due to fibrosis. Herein, we designed a chemo-immuno strategy focused on combining vaccination immunotherapy with multi-targeting sunitinib (SUN) nano-therapy to remodel TME and generate a robust immune response and a stronger synergistic anti-cancer effect. This strategy was evaluated side-by-side with non-Desmoplastic Melanoma and achieved significant improvement in therapeutic efficacy. The combination treatment was also synergistically assessed with the Desmoplastic Melanoma model. This strategy can remodel the fibrotic immunosuppressive TME and result in a robust cytotoxic T-cell response by reducing the collagen content, normalizing blood vessels, inhibiting tumor-associated fibroblasts and reducing high levels of suppressor immune cells. The modification of fibrotic immunosuppressive TME may serve as a good approach to further enhance immunotherapy for Desmoplastic tumors.
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nanocarrier mediated chemo immunotherapy arrested cancer progression and induced tumor dormancy in Desmoplastic Melanoma
ACS Nano, 2018Co-Authors: Qi Liu, Fengqian Chen, Lin Hou, Limei Shen, Xueqiong Zhang, Degeng Wang, Leaf HuangAbstract:In Desmoplastic Melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier-mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing Desmoplastic Melanoma.
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nano delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in Desmoplastic Melanoma
Theranostics, 2018Co-Authors: Lin Hou, Qi Liu, Fengqian Chen, Limei Shen, Xueqiong Zhang, Yun Liu, Leaf HuangAbstract:Rationale: Tumor-associated fibroblasts (TAFs) play a critical role in the suppressive immune tumor microenvironment (TME), compromising the efficacy of immunotherapy. To overcome this therapeutic hurdle, we developed a nanoemulsion (NE) formulation to deliver fraxinellone (Frax), an anti-fibrotic medicine, to TAFs, as an approach to reverse immunosuppressive TME of Desmoplastic Melanoma. Methods: Frax NE was prepared by an ultrasonic emulsification method. The tumor inhibition effect was evaluated by immunofluorescence staining, masson trichrome staining and western blot analysis. Immune cell populations in tumor and LNs were detected by flow cytometry. Results: This Frax NE, with a particle size of around 145 nm, can efficiently accumulate in the tumor site after systemic administration and was taken up by TAFs and tumor cells. A significant decrease in TAFs and stroma deposition was observed after intravenous administration of Frax NE, and Frax NE treatment also remolded the tumor immune microenvironment, as was reflected by an increase of natural-killer cells, cytotoxic T cells (CTLs) as well as a decrease of regulatory B cells, and myeloid-derived suppressor cells in the TME. In addition, after treatment by Frax NEs, T helper 1 (Th1) cytokines of interferon gamma (IFN-γ), which effectively elicit anti-tumor immunity, were enhanced. Transforming growth factor-β (TGF-β), chemokine (C-C motif) ligand 2 (CCL2) and interleukin 6 (IL6), which inhibit the development of anti-tumor immunity, were reduced. Although Frax NE demonstrated an inhibitory effect on tumor growth, this mono-therapy could only achieve partial antitumor efficacy, and the tumor growth effect was not maintained long-term after dosing stopped. Therefore, a tumor-specific peptide vaccine was combined with Frax NEs. The combination led to enhanced tumor-specific T-cell infiltration, activated death receptors on the tumor cell surface, and induced increased apoptotic tumor cell death. Conclusion: Collectively, Frax NE combined with tumor-specific peptide vaccine might be an effective and safe strategy to remodel fibrotic TME, thereby enhancing immune response activation, resulting in a prolonged efficiency for advanced Desmoplastic Melanoma.
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Nanocarrier-Mediated Chemo-Immunotherapy Arrested Cancer Progression and Induced Tumor Dormancy in Desmoplastic Melanoma
2018Co-Authors: Qi Liu, Fengqian Chen, Lin Hou, Limei Shen, Xueqiong Zhang, Degeng Wang, Leaf HuangAbstract:In Desmoplastic Melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier-mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing Desmoplastic Melanoma
Klaus J Busam - One of the best experts on this subject based on the ideXlab platform.
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gene expression signature as an ancillary method in the diagnosis of Desmoplastic Melanoma
Human Pathology, 2017Co-Authors: Loren E Clarke, Jason D Pimentel, Hillary Zalaznick, Lu Wang, Klaus J BusamAbstract:Desmoplastic Melanoma (DM) is a rare fibrosing variant of Melanoma that can be difficult to diagnose. One of the diagnostic challenges is its distinction from a melanocytic nevus with desmoplasia. Here we investigate the use of a 23-gene signature, which has previously been shown to distinguish benign from malignant melanocytic neoplasms. We assessed 50 cases with a differential diagnostic consideration of DM that underwent gene expression testing. Hematoxylin and eosin-stained sections were reviewed, and the final cohort included 20 DMs, 5 nonDesmoplastic Melanomas, and 27 Desmoplastic melanocytic nevi. Of the 20 DMs, the gene expression score was positive ("likely malignant") in 15 tumors, indeterminate in 1, and negative ("likely benign") in 4. None of the Desmoplastic melanocytic nevi were positive. The gene expression score was negative in 24 of the melanocytic nevi and indeterminate in the remaining 3. Nine DMs were also analyzed cytogenetically by single-nucleotide polymorphism (SNP) array. The SNP array revealed chromosomal copy number aberrations consistent with Melanoma in 7 DMs and failed to show any aberrations in 2. The results of SNP array analysis and gene expression testing were discordant in 4 cases. Our results document limitations in the sensitivity of both the gene expression signature and SNP array for the detection of DM. Nonetheless, our findings suggest a potential role of the gene expression signature as ancillary supportive evidence for the distinction of DM from Desmoplastic nevus because positive scores were only seen in Melanomas.
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nf1 mutations are common in Desmoplastic Melanoma
The American Journal of Surgical Pathology, 2015Co-Authors: Thomas Wiesner, Maija Ht Kiuru, Sasinya N Scott, Maria E Arcila, Allan C Halpern, Travis J Hollmann, Michael F Berger, Klaus J BusamAbstract:Desmoplastic Melanoma (DM) is a rare variant of Melanoma with distinct clinical, histopathologic, and immunohistochemical features. Clinically, DM differs from conventional Melanoma by a higher propensity for local recurrence and less frequent metastatic spread to regional lymph nodes. In its pure f
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Desmoplastic Melanoma with sarcomatoid dedifferentiation
The American Journal of Surgical Pathology, 2014Co-Authors: Maija Ht Kiuru, Allan C Halpern, Michael F Berger, Gregory Mcdermott, Klaus J BusamAbstract:Desmoplastic Melanoma (DM) is a variant of Melanoma, which typically affects chronically sun-damaged skin of elderly patients. Pure DM displays a low density of fusiform melanocytes in a collagen-rich matrix. In mixed DM, tumor cell density is higher, and parts of the tumor lack abundant stromal fibrosis. Both pure and mixed DMs usually express S100 protein homogenously. We report herein an unusual biphenotypic tumor characterized by the association of a pure DM with an undifferentiated solid spindle cell nodule. It occurred on the scalp of a 66-year-old man. A biopsy of the undifferentiated spindle cell nodule was initially interpreted at a commercial laboratory as atypical fibroxanthoma. The pure DM was seen only in the excisional specimen. All cells of the pure DM stained for S100 protein and SOX10. The adjacent solid sarcomatoid spindle cell nodule lacked expression of S100 protein, SOX10, as well as melan-A, gp100, and microphthalmia-associated transcription factor in >95% of its tumor cells. Although focal expression of melanocyte differentiation antigens in the solid tumor component made us favor a combined DM with sarcomatoid dedifferentiation, we also considered the possibility of a collision scenario, that is, a pleomorphic dermal sarcoma incidentally colliding with a DM. To further assess a possible relationship of the sarcomatoid nodule with the DM, we performed next-generation sequencing analysis on each component separately. The analysis revealed shared chromosomal copy number changes and a high number of common mutations, thereby supporting the concept of a DM with a dedifferentiated sarcomatoid component. An interesting finding is the presence of mutations of the neurofibromin 1 (NF1) gene in both tumor components.
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Immunohistochemical expression of p16 in Desmoplastic Melanoma.
Journal of Cutaneous Pathology, 2013Co-Authors: Elena Blokhin, Melissa Pulitzer, Klaus J BusamAbstract:Desmoplastic Melanoma can be difficult to distinguish from Desmoplastic melanocytic nevi both clinically and histopathologically. Several attempts have been made to explore the use of ancillary studies to facilitate this distinction. Prior work has suggested that immunohistochemical expression of p16 could help distinguish sclerosing Spitz nevi from Desmoplastic Melanomas. We re-evaluated the expression of p16 in 22 Desmoplastic Melanomas (13 mixed and 9 pure Desmoplastic tumors) and five Desmoplastic melanocytic nevi (three Desmoplastic Spitz nevi and two congenital melanocytic nevi with prominent dermal sclerosis). All Desmoplastic melanocytic nevi were strongly immunoreactive for p16. Of the 22 Desmoplastic Melanomas, 6 tumors failed to label for p16, 10 were focally positive, but 6 tumors were diffusely immunoreactive. The latter finding is relevant, as it points to limitations in the diagnostic value of immunohistochemical staining for p16 for the diagnosis of Desmoplastic melanocytic proliferations. Diffuse staining for p16 is not restricted to Desmoplastic Spitz nevi but can also occur in a subset of Desmoplastic Melanomas, and this warrants caution in the use of this marker for diagnostic purposes.
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Desmoplastic Melanoma a review
Journal of The American Academy of Dermatology, 2013Co-Authors: Lucy Chen, Klaus J Busam, Natalia Jaimes, Christopher A Barker, Ashfaq A MarghoobAbstract:Desmoplastic Melanoma (DM) is a variant of spindle cell Melanoma typically found on chronically sun-damaged skin of older individuals. Early diagnosis can be challenging because it is often amelanotic and has a predominantly dermal component. DM can be difficult to diagnose not only clinically but also histologically, and can be mistaken for a variety of benign and malignant nonmelanocytic spindle cell tumors when viewed on prepared histopathology slides. Pathologists have observed that DMs can manifest significant variation with respect to the extent of intratumoral cellularity, fibrosis, and/or perineural invasion. Furthermore, some tumors present with a pure Desmoplastic invasive component (>90%) while other tumors display mixed features of DM and nonDesmoplastic Melanoma. This has led to the separation of DM into 2 histologic subtypes, pure and mixed. With a focus on the distinction between pure and mixed DM, this review will detail what is currently known about the diagnostic features of DM, discuss risk and prognostic factors, and examine the current literature on disease progression and management.
Richard A Scolyer - One of the best experts on this subject based on the ideXlab platform.
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detection of Desmoplastic Melanoma with dermoscopy and reflectance confocal microscopy
Journal of The European Academy of Dermatology and Venereology, 2017Co-Authors: N G Maher, Richard A Scolyer, Annalisa Solinas, S Puig, Giovanni Pellacani, Pascale GuiteraAbstract:Background Desmoplastic Melanoma (DM) is frequently misdiagnosed clinically and often associated with Melanoma in situ (MIS). Objective To improve the detection of DM using dermoscopy and reflectance confocal microscopy (RCM). Methods A descriptive analysis of DM dermoscopy features and a case-control study within a Melanoma population for RCM feature evaluation, performed blindly, using data obtained between 2005 and 2015. After retrospectively identifying all DM cases with RCM data over the study period (n=16), a control group of non-DM Melanoma patients with RCM data, in a ratio of at least 3:1, was selected. The control group was matched by age and primary tumor site location, divided into non-DM invasive Melanomas (n=27) and MIS (n=27). Invasive Melanomas were selected according to the Melanoma subtypes associated with the DM cases. The main outcomes were the frequency of Melanoma-specific features on dermoscopy for DM; and the odds ratios of RCM features to distinguish DM from MIS and/or other invasive Melanomas; or MIS from the combined invasive Melanoma group. Results At least 1 of the 14 Melanoma-specific features evaluated on dermoscopy were found in 100% of DMs (n=15 DM with dermoscopy). Known RCM Melanoma predictors were commonly found in the DMs, such as pagetoid cells (100%) and cell atypia (100%). The RCM feature of spindle cells in the superficial dermis was more common in DM compared with the entire Melanoma control group (OR 3.82, 95% CI 1.01-14.90), and particularly compared to MIS (OR 5.48, 95% CI 1.11-32.36). Nucleated cells in the dermis and the RCM correlate of dermal inflammation were also significant RCM features favouring DM over MIS, as well as invasive Melanoma over MIS. Conclusion Dermoscopy and RCM may be useful tools for the identification of DM. Certain RCM features may help distinguish DM from MIS and other invasive Melanomas. Larger studies are warranted. This article is protected by copyright. All rights reserved.
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clinical and pathological features of metastases of primary cutaneous Desmoplastic Melanoma
Histopathology, 2011Co-Authors: Stanley W Mccarthy, Richard A Scolyer, Rajmohan Murali, John F Thompson, Diana Zannino, Maria SynnottAbstract:Murali R, Zannino D, Synnott M, McCarthy S W, Thompson J F & Scolyer R A (2011) Histopathology 58, 886–895 Clinical and pathological features of metastases of primary cutaneous Desmoplastic Melanoma Aims: Primary cutaneous Desmoplastic Melanoma (DM) may be entirely Desmoplastic [‘pure’ DM (pDM)] or exhibit a Desmoplastic component admixed with a non-Desmoplastic component [‘combined’ DM (cDM)]. Our aim was to describe the histological features of metastases of primary DM and to determine whether they were predictive of outcome. Methods: The effect of clinicopathological parameters on overall survival (OS) was analysed, and the correlation between histological features of the primary Melanoma and metastases was studied in patients with metastatic DM. Results: Twenty-six patients (18 males; eight females) developed 50 metastases in sentinel nodes (13; 26.0%), regional nodes (10; 20.0%), skin (14; 28.0%), and distant sites (13; 26.0%). The cellular composition of metastases correlated with that of the corresponding primary tumours. Time to development of first non-sentinel lymph node metastasis was shorter in cDM than in pDM (median 11.2 versus 24.9 months, P = 0.075). The only independent predictors of poorer OS were cDM type [hazard ratio 6.17, 95% confidence interval (CI) 1.61–23.81, P = 0.008] and male sex (hazard ratio 5.98, 95% CI 1.34–26.66, P = 0.019). Conclusions: The cellular composition of primary DM correlates with that of metastatic DM and with outcome. It is important to consider the possibility of primary or metastatic DM when examining tumours composed of spindle cells.
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27 pathological features of metastases from primary cutaneous Desmoplastic Melanoma
Pathology, 2011Co-Authors: Stanley W Mccarthy, Richard A Scolyer, Rajmohan Murali, John F Thompson, Diana Zannino, Maria SynnottAbstract:Background Desmoplastic Melanoma (DM) is characterised by malignant spindle cells associated with prominent fibrocollagenous stroma. Primary Melanomas may be entirely Desmoplastic (‘pure’ DM, pDM) or exhibit a Desmoplastic component admixed with a non-Desmoplastic component (‘combined’DM, cDM).Wesoughtto correlate the features of primary DM with those of metastases. Methods The study cohort included patients with metastatic DM, in whom slides from the primary and metastatic tumours were available for review. Correlation between histological features of the primary Melanoma and metastases was analysed. The effect of clinico-pathological parameters on overall survival (OS) and SLN positivity was analysed. Results 26 patients (18 males, 8 females) developed 50 metastases. Metastases from primary cDM more commonly (53.2%) involved lymph nodes than those from primary pDM (33.4%; p = 0.03). Primary Melanomas composed predominantly of spindle cells were associated with increasing % of spindle cells ( r = 0.40, p = 0.007) and decreasing % of epithelioid cells ( r = –0.41, p = 0.005) in the metastases. Primary pDM was strongly associated with extensive desmoplasia in the MM (r = 0.57, p p =0.08). Independent predictors of poorerOSwere cDM type(hazard ratio6.17,95%CI1.61–23.81) and male sex (hazard ratio 5.98, 95%CI 1.34–26.66). Conclusions The cellular composition of metastases from primary cutaneous DM correlate with the composition of the primary tumours. It is important to consider the possibility of primary or metastatic Desmoplastic Melanoma when examining tumours composed of spindle cells.
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prognostic factors in cutaneous Desmoplastic Melanoma a study of 252 patients
Cancer, 2010Co-Authors: Stanley W Mccarthy, Rajmohan Murali, John F Thompson, Jonathan R Stretch, Helen M Shaw, Kenneth Lai, Michael J Quinn, Richard A ScolyerAbstract:BACKGROUND: Desmoplastic Melanoma (DM) is a rare subtype of Melanoma that is characterized by malignant spindle cells separated by prominent, fibrocollagenous stroma. Primary Melanomas either may be entirely Desmoplastic or almost entirely Desmoplastic (pure DM [pDM]) or may exhibit a Desmoplastic component admixed with a nonDesmoplastic component (combined DM [cDM]). METHODS: Patients who were diagnosed between 1993 and 2007 at a single institution with clinically localized, primary cutaneous Melanoma (PCM) that contained a Desmoplastic component and who underwent sentinel lymph node (SLN) biopsy were identified. Clinical and pathologic features of the primary tumors were correlated with DM type, SLN status, and patient outcome. RESULTS: Two hundred fifty-two patients (167 men, 85 women) were identified (median age, 61 years). The median tumor thickness was 2.0 mm. One hundred twenty-three patients (48.8%) had pDM, and 129 patients (51.2%) had cDM. Overall, 17 patients (6.7%) had positive SLN status, including 12 patients with cDM and 5 patients with pDM. Because of the low SLN-positive rate, a statistically significant difference in SLN status between patients with cDM (8.5%) and patients with pDM (4.9%; P = .25) could not be demonstrated. Older patient age, being a man, positive SLN status, and increasing tumor thickness were associated significantly with poorer disease-free survival (P < .05), although only the latter 2 variables were independently predictive. In addition, cDM type (P = .017) was associated significantly and independently with a shorter time to recurrence. CONCLUSIONS: In this largest study to date of patients with DM who underwent SLN biopsy, the SLN-positive rate in patients with DM was lower than that in patients with conventional Melanoma. The results indicated that DM type is associated significantly and independently with the time to recurrence and should be evaluated routinely in all patients with PCM. Cancer 2010. © 2010 American Cancer Society.
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cytologic features of metastatic and recurrent Melanoma in patients with primary cutaneous Desmoplastic Melanoma
American Journal of Clinical Pathology, 2008Co-Authors: Richard A Scolyer, Rajmohan Murali, Noel T Loughman, Paul R Mckenzie, Geoffrey F Watson, John F ThompsonAbstract:Desmoplastic Melanoma (DM) is a rare subtype of Melanoma characterized by malignant spindle cells associated with prominent fibrocollagenous stroma. Primary Melanomas may be entirely Desmoplastic (“pure” DM) or exhibit a Desmoplastic component admixed with a nonDesmoplastic component
Qi Liu - One of the best experts on this subject based on the ideXlab platform.
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remodeling the fibrotic tumor microenvironment of Desmoplastic Melanoma to facilitate vaccine immunotherapy
Nanoscale, 2020Co-Authors: Hongda Zhu, Qi Liu, Lei Miao, Sara Musetti, Meirong Huo, Leaf HuangAbstract:Highly fibrotic and collagen-rich properties in Desmoplastic Melanoma (DM) result in an immune-suppressive fibrotic tumor microenvironment (TME) that resists clinical therapies. The different clinical and pathological properties, as compared to conventional Melanoma, lead to delayed diagnosis and it is difficult to deliver drugs effectively due to fibrosis. Herein, we designed a chemo-immuno strategy focused on combining vaccination immunotherapy with multi-targeting sunitinib (SUN) nano-therapy to remodel TME and generate a robust immune response and a stronger synergistic anti-cancer effect. This strategy was evaluated side-by-side with non-Desmoplastic Melanoma and achieved significant improvement in therapeutic efficacy. The combination treatment was also synergistically assessed with the Desmoplastic Melanoma model. This strategy can remodel the fibrotic immunosuppressive TME and result in a robust cytotoxic T-cell response by reducing the collagen content, normalizing blood vessels, inhibiting tumor-associated fibroblasts and reducing high levels of suppressor immune cells. The modification of fibrotic immunosuppressive TME may serve as a good approach to further enhance immunotherapy for Desmoplastic tumors.
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nanocarrier mediated chemo immunotherapy arrested cancer progression and induced tumor dormancy in Desmoplastic Melanoma
ACS Nano, 2018Co-Authors: Qi Liu, Fengqian Chen, Lin Hou, Limei Shen, Xueqiong Zhang, Degeng Wang, Leaf HuangAbstract:In Desmoplastic Melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier-mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing Desmoplastic Melanoma.
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nano delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in Desmoplastic Melanoma
Theranostics, 2018Co-Authors: Lin Hou, Qi Liu, Fengqian Chen, Limei Shen, Xueqiong Zhang, Yun Liu, Leaf HuangAbstract:Rationale: Tumor-associated fibroblasts (TAFs) play a critical role in the suppressive immune tumor microenvironment (TME), compromising the efficacy of immunotherapy. To overcome this therapeutic hurdle, we developed a nanoemulsion (NE) formulation to deliver fraxinellone (Frax), an anti-fibrotic medicine, to TAFs, as an approach to reverse immunosuppressive TME of Desmoplastic Melanoma. Methods: Frax NE was prepared by an ultrasonic emulsification method. The tumor inhibition effect was evaluated by immunofluorescence staining, masson trichrome staining and western blot analysis. Immune cell populations in tumor and LNs were detected by flow cytometry. Results: This Frax NE, with a particle size of around 145 nm, can efficiently accumulate in the tumor site after systemic administration and was taken up by TAFs and tumor cells. A significant decrease in TAFs and stroma deposition was observed after intravenous administration of Frax NE, and Frax NE treatment also remolded the tumor immune microenvironment, as was reflected by an increase of natural-killer cells, cytotoxic T cells (CTLs) as well as a decrease of regulatory B cells, and myeloid-derived suppressor cells in the TME. In addition, after treatment by Frax NEs, T helper 1 (Th1) cytokines of interferon gamma (IFN-γ), which effectively elicit anti-tumor immunity, were enhanced. Transforming growth factor-β (TGF-β), chemokine (C-C motif) ligand 2 (CCL2) and interleukin 6 (IL6), which inhibit the development of anti-tumor immunity, were reduced. Although Frax NE demonstrated an inhibitory effect on tumor growth, this mono-therapy could only achieve partial antitumor efficacy, and the tumor growth effect was not maintained long-term after dosing stopped. Therefore, a tumor-specific peptide vaccine was combined with Frax NEs. The combination led to enhanced tumor-specific T-cell infiltration, activated death receptors on the tumor cell surface, and induced increased apoptotic tumor cell death. Conclusion: Collectively, Frax NE combined with tumor-specific peptide vaccine might be an effective and safe strategy to remodel fibrotic TME, thereby enhancing immune response activation, resulting in a prolonged efficiency for advanced Desmoplastic Melanoma.
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Nanocarrier-Mediated Chemo-Immunotherapy Arrested Cancer Progression and Induced Tumor Dormancy in Desmoplastic Melanoma
2018Co-Authors: Qi Liu, Fengqian Chen, Lin Hou, Limei Shen, Xueqiong Zhang, Degeng Wang, Leaf HuangAbstract:In Desmoplastic Melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier-mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing Desmoplastic Melanoma
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Immunotherapy for Desmoplastic Melanoma: nano-medicine approaches of vaccination and immune-modulation
University of North Carolina at Chapel Hill Graduate School, 2018Co-Authors: Qi LiuAbstract:Melanoma, the most lethal skin cancer, has an incremental incidence, few durable therapies, and a low survival rate of less than 10 % for late-stage patients in clinics. In Desmoplastic Melanoma, a rare histological variant of Melanoma, the highly fibrotic morphology as well as the immune-suppressive tumor microenvironment led to distinct clinical behavior when compared with other Melanoma subtypes, thus hindering treatment efficacy. To overcome these therapeutic hurdles, herein in this dissertation work I developed multiple innovative strategies based on targeted nano-delivery systems. These strategies include the effective delivery of therapeutic vaccination, immune-modulating chemo-drugs and active compounds, gene therapy, and a combination of chemo-immune initiated/guided treatment. A total of five aims were sequentially designed, including 1) nano-vaccination. The tumor-specific antigen peptides were efficiently delivered to antigen-presenting cells along with immune-stimulating adjuvant. This therapeutic vaccine inhibited aggressive tumor growth. 2) nano-sunitinib. The FDA approved drug sunitinib was targeted delivered to the tumor with improved anti-tumor efficacy, furthermore, it largely remodeled immune suppressive microenvironment and facilitated vaccination efficacy. 3) nano-fraxinellone. The active compound fraxinellone was nano-delivered to the tumor microenvironment, inhibiting the transition of tumor associated fibroblasts and skewed TGF-β/IFN- γ balancing toward pro-inflammatory settings. 4) nano-wnt5a trap. Key molecular wnt5a secreted by tumor cells in inducing dendritic cell tolerance and tumor fibrosis was locally trapped, thus significantly tuned immune recognition and surveillance of cancer progression. 5) nano-delivery of mitoxantrone and celastrol. Two drugs were screened out with highest anti-tumor and anti-fibrosis potentials and worked synergistically in inducing immunogenic tumor cell death and long-term memory immune responses. Using animal models of Desmoplastic Melanoma, our nanomedicine designs significantly elicited an overall anti-tumor immunity with increased efficacy, safety profiles, and prolonged host survival, suggesting their high translatability to the clinic. This dissertation research work further sheds light on a deeper understanding of cancer type-specific microenvironment and immune modulators, as well as future mechanism studies in designing immunotherapy for Desmoplastic Melanoma.Doctor of Philosoph
Lin Hou - One of the best experts on this subject based on the ideXlab platform.
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nanocarrier mediated chemo immunotherapy arrested cancer progression and induced tumor dormancy in Desmoplastic Melanoma
ACS Nano, 2018Co-Authors: Qi Liu, Fengqian Chen, Lin Hou, Limei Shen, Xueqiong Zhang, Degeng Wang, Leaf HuangAbstract:In Desmoplastic Melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier-mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing Desmoplastic Melanoma.
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nano delivery of fraxinellone remodels tumor microenvironment and facilitates therapeutic vaccination in Desmoplastic Melanoma
Theranostics, 2018Co-Authors: Lin Hou, Qi Liu, Fengqian Chen, Limei Shen, Xueqiong Zhang, Yun Liu, Leaf HuangAbstract:Rationale: Tumor-associated fibroblasts (TAFs) play a critical role in the suppressive immune tumor microenvironment (TME), compromising the efficacy of immunotherapy. To overcome this therapeutic hurdle, we developed a nanoemulsion (NE) formulation to deliver fraxinellone (Frax), an anti-fibrotic medicine, to TAFs, as an approach to reverse immunosuppressive TME of Desmoplastic Melanoma. Methods: Frax NE was prepared by an ultrasonic emulsification method. The tumor inhibition effect was evaluated by immunofluorescence staining, masson trichrome staining and western blot analysis. Immune cell populations in tumor and LNs were detected by flow cytometry. Results: This Frax NE, with a particle size of around 145 nm, can efficiently accumulate in the tumor site after systemic administration and was taken up by TAFs and tumor cells. A significant decrease in TAFs and stroma deposition was observed after intravenous administration of Frax NE, and Frax NE treatment also remolded the tumor immune microenvironment, as was reflected by an increase of natural-killer cells, cytotoxic T cells (CTLs) as well as a decrease of regulatory B cells, and myeloid-derived suppressor cells in the TME. In addition, after treatment by Frax NEs, T helper 1 (Th1) cytokines of interferon gamma (IFN-γ), which effectively elicit anti-tumor immunity, were enhanced. Transforming growth factor-β (TGF-β), chemokine (C-C motif) ligand 2 (CCL2) and interleukin 6 (IL6), which inhibit the development of anti-tumor immunity, were reduced. Although Frax NE demonstrated an inhibitory effect on tumor growth, this mono-therapy could only achieve partial antitumor efficacy, and the tumor growth effect was not maintained long-term after dosing stopped. Therefore, a tumor-specific peptide vaccine was combined with Frax NEs. The combination led to enhanced tumor-specific T-cell infiltration, activated death receptors on the tumor cell surface, and induced increased apoptotic tumor cell death. Conclusion: Collectively, Frax NE combined with tumor-specific peptide vaccine might be an effective and safe strategy to remodel fibrotic TME, thereby enhancing immune response activation, resulting in a prolonged efficiency for advanced Desmoplastic Melanoma.
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Nanocarrier-Mediated Chemo-Immunotherapy Arrested Cancer Progression and Induced Tumor Dormancy in Desmoplastic Melanoma
2018Co-Authors: Qi Liu, Fengqian Chen, Lin Hou, Limei Shen, Xueqiong Zhang, Degeng Wang, Leaf HuangAbstract:In Desmoplastic Melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death. Here, we show that when effectively co-delivered to the tumor site at their optimal ratio by a TME-responsive nanocarrier, the 5:1 combination of MIT and CEL significantly triggered immunogenic tumor apoptosis and recovered tumor antigen recognition, thus eliciting overall antitumor immunity. Furthermore, the strong synergy benefitted the host in reduced drug exposure and side effects. Collectively, the nanocarrier-mediated chemo-immunotherapy successfully remodeled fibrotic and immunosuppressive TME, arrested cancer progression, and further inhibited tumor metastasis to major organs. The affected tumors remained dormant long after dosing stopped, resulting in a prolonged progression-free survival and sustained immune surveillance of the host bearing Desmoplastic Melanoma