RESUMEN
Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Acrilamidas , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Endorribonucleasas , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Mutación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Nucleotidiltransferasas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina QuinasasRESUMEN
In this work we eluted peptides from purified class I MHC molecules, isolated from a novel human cervical carcinoma cell line (INBL), generated in our laboratory and positive for HPV-18 infection. A fraction of these peptides was capable of stimulating T lymphocytes obtained from a donor matched for HLA-Cw4 and who was also HPV-18+. Direct N-terminal Edman degradation of these peptides, revealed the sequence (XQFPIFLQF) that matched 85% with the sequence NVFPIFLQM localized in between the 54 and 62 residues of the HPV-18 L1 protein. After stimulation with the synthetic peptide NVFPIFLQM, T lymphocytes from the donor were capable to lyse INBL cells. Our results provide evidence of the existence of naturally occurring viral epitopes presented on cervical cancer cells by the HLA-Cw4 allele, that could be useful for immunotherapy on this type of patient.
Asunto(s)
Antígenos de Histocompatibilidad Clase I/inmunología , Papillomaviridae/inmunología , Péptidos/inmunología , Neoplasias del Cuello Uterino/virología , Proteínas Virales/inmunología , Secuencia de Aminoácidos , Antígenos Virales/química , Antígenos Virales/inmunología , Citotoxicidad Inmunológica , Epítopos/inmunología , Femenino , Antígenos de Histocompatibilidad Clase I/química , Humanos , Activación de Linfocitos , Espectrometría de Masas , Datos de Secuencia Molecular , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/virología , Péptidos/química , Péptidos/aislamiento & purificación , Linfocitos T/inmunología , Células Tumorales Cultivadas , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Neoplasias del Cuello Uterino/inmunología , Proteínas Virales/química , Proteínas Virales/aislamiento & purificaciónRESUMEN
Receptors for the Fc fragment of immunoglobulins G (Fc gamma R) belong to the immunoglobulin superfamily and are expressed on different cell types. These receptors are classified in three different groups (Fc gamma RI, Fc gamma RII and Fc gamma RIII) depending upon their molecular weight, affinity and specificity for their ligands. In addition to all these differences, genetic polymorphisms induce the expression of several isoforms, making the Fc gamma R a heterogeneous group. The Fc gamma Rs have been the subject of intense research on their gene organization, biochemical and structural properties. It has also been established that the Fc gamma R play an important functional role on the regulation of the biological responses that are triggered during inflammatory stages (e.g. an infection), as they link the cellular and humoral branches of the immune response. In this article we give examples of the participation of Fc gamma R on the regulation of the immune response as well as the activation of intracellular mechanisms (transduction signals) after the crosslinking of Fc gamma R by antigen-antibody complexes. The effect of cytokines and growth factors on the regulation of Fc gamma R expression is also described. We discuss the importance of the possible use of some of these molecules to control the expression of Fc gamma R in some clinical situations where alterations on their expression are associated with some diseases. Finally, we analyze the role of Fc gamma R as the point of entry of infectious agents such as HIV.