RESUMEN
A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.
Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Resistencia a Antineoplásicos/inmunología , Neoplasias/tratamiento farmacológico , Proclorperazina/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados/farmacología , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Presentación de Antígeno/efectos de los fármacos , Biopsia , Cetuximab/farmacología , Sistemas de Liberación de Medicamentos/métodos , Resistencia a Antineoplásicos/genética , Endocitosis/efectos de los fármacos , Endocitosis/inmunología , Xenoinjertos , Humanos , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células MCF-7 , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Neoplasias/genética , Neoplasias/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Trastuzumab/farmacologíaRESUMEN
Introduction: Cutaneous squamous cell carcinoma of the head and neck (cSCCHN) can metastasize by invading nerves and spread toward the central nervous system. This metastatic process is called perineural invasion (PNI) and spread (PNS). An in vivo sciatic nerve mouse model is used for cSCCHN PNI/PNS. Here we describe a complementary whisker pad model which allows for molecular studies investigating drivers of PNI/PNS in the head and neck environment. Methods: A431 cells were injected into the whisker pads of BALB/c Foxn1nu and NSG-A2 mice. Tumor progression was monitored by bioluminescence imaging and primary tumor resection was performed. PNI was detected by H&E and IHC. Tumor growth and PNI were assessed with inducible ablation of LOXL2. Results: The rate of PNI development in mice was 10%-28.6%. Tumors exhibited PNI/PNS reminiscent of the morphology seen in the human disease. Our model's utility was demonstrated with inducible ablation of LOXL2 reducing primary tumor growth and PNI. Discussion: This model consists in a feasible way to test molecular characteristics and potential therapies, offers to close a gap in the described in vivo methods for PNI/PNS of cSCCHN and has uses in concert with the established sciatic nerve model.