RESUMEN
PURPOSE: To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor microenvironment (TME) abnormalities, enhancing the efficacy of immune-checkpoint inhibitors in sarcoma. EXPERIMENTAL DESIGN: We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti-PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurposed phase II clinical trial. RESULTS: Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemoimmunotherapy, supported by enhanced T-cell infiltration and acquisition of tumor antigen-specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients, highlighting its translational potential. CONCLUSIONS: Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.
Asunto(s)
Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico , Mastocitos , Microambiente Tumoral , Humanos , Ratones , Animales , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Sarcoma/inmunología , Cetotifen/farmacología , Cetotifen/uso terapéutico , Línea Celular Tumoral , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Femenino , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/patología , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Osteosarcoma/inmunologíaRESUMEN
Mechanical stresses in solid tumors play an important role in tumor progression and treatment efficacy but their quantification is under-investigated. Here, we developed an experimental and computational approach to calculate growth-induced, residual stresses and applied it to the breast (4T1), pancreatic (PAN02), and fibrosarcoma (MCA205) tumor models. Following resection, tumors are embedded in agarose gels and cuts are made in two perpendicular directions to release residual stress. With the use of image processing, the detailed bulging displacement profile is measured and finite elements models of the bulging geometry are developed for the quantification of the stress levels. The mechanical properties of the tumors are measured in vivo prior to resection with shear wave elastography. We find that the average magnitude of residual stresses ranges from 3.31 to 10.88 kPa, and they are non-uniformly distributed within the tissue due to the heterogeneity of the tumor microenvironment. Interestingly, we demonstrate that a second cut can still release a significant amount of stresses. We further find a strong association of spatial hyaluronan and collagen content with the spatial profile of stress for the MCA205 and PAN02 tumors and a partial association for the 4T1. Interestingly the colocalization of hyaluronan and collagen content had a stronger association with the spatial profile of stress for MCA205, PAN02, and 4T1. Finally, measurements of the elastic modulus with shear wave elastography show a nonlinear correlation with tumor volume for the more fibrotic MCA205 and 4T1 tumors. Overall, our results provide insights for a better understanding of the mechanical behavior of tumors.