RESUMEN

In triple-negative breast cancer (TNBC), the tumor immune microenvironment (TIME) is a highly heterogeneous ecosystem that exerts indispensable roles in tumorigenesis and tumor progression. Cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs) are the main matrix components in the TIME of TNBC. CAFs mediate the edesmoplastic response, which is a major driver of the immunosuppressive microenvironment to promote tumor growth. In addition, CAAs, a type of tumor-educated adipocyte, participate in crosstalk with breast cancer and are capable of secreting various cytokines, adipokines and chemokines, especially C-C Motif Chemokine Ligand 2 (CCL2), resulting in changes of cancer cell phenotype and function. Therefore, how to treat tumors by regulating the CAFs and the secretion of CCL2 by CAAs in TIME is investigated here. Our research group previously found that rhein (Rhe) has been identified as effective against CAFs, while hesperidin (Hes) could effectively diminish CCL2 secretion by CAAs. Inspired by the above, we developed unique PLGA-based nanoparticles loaded with Rhe and Hes (RH-NP) using the emulsion solvent diffusion method. The RH-NP particles have an average size of 114.1 ± 0.98 nm. RH-NP effectively reduces CAFs and inhibits CCL2 secretion by CAAs, promoting increased infiltration of cytotoxic T cells and reducing immunosuppressive cell presence within tumors. This innovative, safe, low-toxic, and highly effective anti-tumor strategy could be prospective in TNBC treatment.

Asunto(s)

Antraquinonas , Fibroblastos Asociados al Cáncer , Quimiocina CCL2 , Hesperidina , Nanopartículas , Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Quimiocina CCL2/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/inmunología , Femenino , Humanos , Hesperidina/farmacología , Hesperidina/uso terapéutico , Animales , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/metabolismo , Nanopartículas/química , Línea Celular Tumoral , Antraquinonas/farmacología , Antraquinonas/uso terapéutico , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/inmunología , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química

RESUMEN

Triple negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer characterized by an unfavorable prognosis due to its aggressive biology. Cancer-associated adipocytes (CAAs) play an active role in tumor development, invasion and metastasis, and response to treatment by secreting various cytokines. CAAs secrete CCL2 and ADPN which significantly affect the efficacy of aPD-1 in treating breast cancer. Our recent research has demonstrated that Hesperidin, a natural phenolic compound, significantly inhibits CCL2, elevates ADPN secreted by CAAs in vitro and in vivo, remodels the immune microenvironment, and potentiates the efficacy of aPD-1 in triple-negative breast cancer. We used Oil red staining, Bodipy 493/503 staining and quantitative real-time PCR to verify the formation of CAAs. ELISA was used to detect levels of CCL2, ADPN secreted by CAAs. Changes in the number of immune cells in mouse tumor tissues were detected using flow cytometry and immunofluorescence. Our data suggest that Hesperidin PLGA nanoparticles significantly reduced CCL2 and increased ADPN secreted by CAAs, which concurrently decreased the recruitment of M2 macrophages, Tregs and MDSCs while increased the infiltration of CD8+T cells, M1 macrophages and DCs into tumor, thus significantly potentiated the efficacy of aPD-1 in vivo. This study provides a new combined strategy for the clinical treatment of triple-negative breast cancer by interfering with CCL2, ADPN secreted by CAAs to enhance the efficacy of immunotherapy.

Asunto(s)

Adipocitos , Quimiocina CCL2 , Hesperidina , Nanopartículas , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Hesperidina/farmacología , Hesperidina/uso terapéutico , Femenino , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Humanos , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Línea Celular Tumoral , Ratones , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Ratones Endogámicos BALB C , Adipoquinas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Sinergismo Farmacológico

RESUMEN

BACKGROUND: The prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) is closely related to the increase of the incidence rate of obesity. AIMS: To find out the targets of celastrol on NAFLD with the treatment of celastrol-loaded liposomes (Cel-Lips). METHODS: Gene Expression Omnibus (GEO) data were used to compare the expression of differential genes in NAFLD patients with normal individuals. Celastrol was loaded into liposomes to improve its solubility, as well as, achieving a passive targeting effect on the liver to improve the availability, which also could delay the release rate of celastrol to prolong the action time and thus reduce the frequency of administration. Due to rarely reported molecular mechanisms of celastrol, with the help of network pharmacological analysis, the targets of celastrol acting on NAFLD were predictively analyzed. RESULTS: An association between NAFLD and lipid metabolism was detected in GEO data. Cel-Lips significantly alleviated NAFLD in vivo. Through network pharmacology, it was found that most of the action pathways of celastrol were related to lipid metabolism. CONCLUSION: Celastrol has the potential to treat NAFLD, and its possible targets have been identified through network pharmacological screening, which provides a certain basis for the follow-up researches.

RESUMEN

Cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cells in the tumor microenvironment which mediate desmoplastic response and are the primary driver for an immunosuppressive microenvironment, leading to the failure of triple-negative breast cancer (TNBC) immunotherapy. Therefore, depleting CAFs may enhance the effect of immunotherapy (such as PD-L1 antibody). Relaxin (RLN) has been demonstrated to significantly improve transforming growth factor-ß (TGF-ß) induced CAFs activation and tumor immunosuppressive microenvironment. However, the short half-life and systemic vasodilation of RLN limit its in vivo efficacy. Here, plasmid encoding relaxin (pRLN) to locally express RLN was delivered with a new positively charged polymer named polymeric metformin (PolyMet), which could increase gene transfer efficiency significantly and have low toxicity that have been certified by our lab before. In order to improve the stability of pRLN in vivo, this complex was further formed lipid poly-γ-glutamic acid (PGA)/PolyMet-pRLN nanoparticle (LPPR). The particle size of LPPR was 205.5 ± 2.9 nm, and the zeta potential was +55.4 ± 1.6 mV. LPPR displayed excellent tumor penetrating efficacy and weaken proliferation of CAFs in 4T1luc/CAFs tumor spheres in vitro. In vivo, it could reverse aberrantly activated CAFs by decreasing the expression of profibrogenic cytokine and remove the physical barrier to reshape the tumor stromal microenvironment, which enabled a 2.2-fold increase in cytotoxic T cell infiltration within the tumor and a decrease in immunosuppressive cells infiltration. Thus, LPPR was observed retarded tumor growth by itself in the 4T1 tumor bearing-mouse, and the reshaped immune microenvironment further led to facilitate antitumor effect when it combined with PD-L1 antibody (aPD-L1). Altogether, this study presented a novel therapeutic approach against tumor stroma using LPPR to achieve a combination regimen with immune checkpoint blockade therapy against the desmoplastic TNBC model.