Revistas
Revista:
CELL REPORTS MEDICINE
ISSN:
2666-3791
Año:
2023
Vol.:
4
N°:
3
Págs.:
100978
Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previ-ously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their sys-temic therapeutic efficacy when delivered intratumorally. Here, we mix T cells engineered with mRNAs to ex-press either single-chain IL-12 (scIL-12) or an IL-18 decoy-resistant variant (DRIL18) that is not functionally hampered by IL-18 binding protein (IL-18BP). These mRNA-engineered T cell mixtures are repeatedly in-jected into mouse tumors. Pmel-1 T cell receptor (TCR)-transgenic T cells electroporated with scIL-12 or DRIL18 mRNAs exert powerful therapeutic effects in local and distant melanoma lesions. These effects are associated with T cell metabolic fitness, enhanced miR-155 control on immunosuppressive target genes, enhanced expression of various cytokines, and changes in the glycosylation profile of surface proteins, enabling adhesiveness to E-selectin. Efficacy of this intratumoral immunotherapeutic strategy is recapitu-lated in cultures of tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells on IL -12 and DRIL18 mRNA electroporation.
Revista:
CANCER DISCOVERY
ISSN:
2159-8274
Año:
2022
Vol.:
12
N°:
9
Págs.:
2140 - 2157
Interleukin-8 (CXCL8) produced in the tumor microenvironment correlates with poor response to checkpoint inhibitors and is known to chemoattract and activate immunosuppressive myeloid leukocytes. In human cancer, IL8 mRNA levels correlate with IL1B and TNF transcripts. Both cytokines induced IL-8 functional expression from a broad variety of human cancer cell lines, primary colon carcinoma organoids, and fresh human tumor explants. Although IL8 is absent from the mouse genome, a similar murine axis in which TNF alpha and IL-1 beta upregulate CXCL1 and CXCL2 in tumor cells was revealed. Furthermore, intratumoral injection of TNF alpha and IL-1 beta induced IL-8 release from human malignant cells xenografted in immunodeficient mice. In all these cases, the clinically used TNF alpha blockers infliximab and etanercept or the IL-1 beta inhibitor anakinra was able to interfere with this pathogenic cytokine loop. Finally, in paired plasma samples of patients with cancer undergoing TNF alpha blockade with infliximab in a clinical trial, reductions of circulating IL-8 were substantiated. SIGNIFICANCE IL-8 attracts immunosuppressive protumor myeloid cells to the tumor microenvironment, and IL-8 levels correlate with poor response to checkpoint inhibitors. TNF alpha and IL-1 beta are identified as major inducers of IL-8 expression on malignant cells across cancer types and models in a manner that is druggable with clinically available neutralizing agents.
Revista:
CLINICAL CANCER RESEARCH
ISSN:
1078-0432
Año:
2022
Vol.:
28
N°:
10
Págs.:
1993 - 1995
Ovarian cancer is often limited to the peritoneal cavity in the form of peritoneal carcinomatosis. Peritoneal spreading offers the opportunity for locoregional delivery of combinations of immuno- therapy agents, maximizing bioavailability while potentially reduc-ing systemic exposure and side effects.
Revista:
JOURNAL OF PATHOLOGY
ISSN:
0022-3417
Año:
2021
Vol.:
255
N°:
2
Págs.:
190 - 201
Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8(+) T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8(+) T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8(+) T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8(+) tumour-infiltrating lymphocytes. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Revista:
CLINICAL CANCER RESEARCH
ISSN:
1078-0432
Año:
2021
Vol.:
27
N°:
2
Págs.:
374 - 376
It has been reported that a group of patients with advanced non- small cell lung cancer showed circulating T cells with a senescent phenotype, and an abundance of such cells is associated with worse clinical response to immune checkpoint inhibitors. This study encourages further analysis of the role of senescent T cells in resistance to lung cancer immunotherapy.
Revista:
JOURNAL OF THORACIC ONCOLOGY
ISSN:
1556-0864
Año:
2020
Vol.:
15
N°:
4
Págs.:
489 - 492
Revista:
NATURE CANCER
ISSN:
2662-1347
Año:
2020
Vol.:
1
Págs.:
75 - 85
Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/Treg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1¿programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.
Revista:
LUNG CANCER
ISSN:
0169-5002
Año:
2018
Vol.:
122
Págs.:
120 - 123
BACKGROUND:
The differential diagnosis between multiple primary lung cancer (MPLC) and advanced lung cancer has traditionally relied on conventional radiology and pathology. However, the outcomes of traditional diagnostic workup are often limited, and staging is uncertain. Increasing evidence suggests that next-generation sequencing (NGS) techniques offer the possibility of comparing multiple tumors on a genomic level.
OBJECTIVES:
The objective of this study is to assess the clinical impact utility of targeted sequencing in patients presenting with multiple synchronous or metachronous lung tumors.
MATERIALS AND METHODS:
We describe the diagnostic workup conducted in a patient with three lung tumors, where we used a targeted 50-gene DNA sequencing panel (Ion AmpliSeq TM Cancer Hotspot Panel v2) to assess clonality and establish an accurate lung adenocarcinoma stage. Positive results were confirmed by pyrosequencing or Sanger sequencing.
RESULTS:
Three surgically resected lung tumors were submitted for targeted sequencing. The tumor from the upper right lobe was positive for a TP53 c.659A¿>¿G mutation and native for KRAS. The tumor from the upper left lobe was positive for TP53 c.725G¿>¿T and KRAS c.35G¿>¿T mutations. The tumor from the lower left lobe was positive for TP53 c.1024C¿>¿T and KRAS C.34G¿>¿T mutations. Results and reviewed literature in the field support the diagnosis of MPLC instead of a single advanced lung cancer.
CONCLUSION:
Targeted DNA sequencing significantly increases diagnostic accuracy in patients with multiple lung tumors. NGS panels should be available for patients presenting with multiple lung tumors.
Nacionales y Regionales
Título:
Trampas Extracelulares de Neutrófilos en el Microambiente de Tumores Sólidos: Hacia un Biomarcador de Inmunoterapia.
Código de expediente:
PI21/01547
Investigador principal:
Carlos Eduardo De Andrea
Financiador:
INSTITUTO DE SALUD CARLOS III
Convocatoria:
2021 AES Proyectos de investigación
Fecha de inicio:
01/01/2022
Fecha fin:
31/12/2024
Importe concedido:
159.720,00€
Otros fondos:
Fondos FEDER
Título:
Modelando inmnunoterapia del cáncer de riñón en ratones humanizados
Código de expediente:
PI19/00668
Investigador principal:
Miguel Fernández de Sanmamed Gutiérrez
Financiador:
INSTITUTO DE SALUD CARLOS III
Convocatoria:
2019 AES Proyectos de investigación
Fecha de inicio:
01/01/2020
Fecha fin:
31/12/2023
Importe concedido:
111.320,00€
Otros fondos:
Fondos FEDER
Otros (PIUNA, fundaciones, contratos…)
Título:
Translational Research for BI 765179 CD137/FAP Agonist in a
Investigador principal:
Ignacio Javier Melero Bermejo, Carlos Eduardo De Andrea
Fecha de inicio:
15/02/2023
Fecha fin:
15/02/2025
Importe:
625.125,00€
Otros fondos:
-
Título:
IL-8/CXCR pathway modulation plus CD137 co-stimulation as a way to overcome resistance to PD-1/PD-L1 pathway blockade in melanoma and kidney cancer patients
Código de expediente:
LABAE211756FERN
Investigador principal:
Miguel Fernández de Sanmamed Gutiérrez
Financiador:
ASOCIACION ESPAÑOLA CONTRA EL CANCER
Convocatoria:
2021 AECC Lab AYUDAS A PROYECTOS DE INVESTIGACIÓN (Grupos emergentes)
Fecha de inicio:
01/12/2021
Fecha fin:
30/11/2024
Importe concedido:
300.000,00€
Título:
Utilidad de la biopsia líquida en la detección de los mecanismos de resistencia al tratamiento con inhibidores de tirosina quinasa en pacientes con carcinoma no microcítico de pulmón (CNMP) avanzado y/o metastásico con presencia de translocaciones de ALK o ROS-1.
Código de expediente:
2018-04
Investigador principal:
Eduardo Castañón Álvarez, Estíbaliz Alegre Martínez
Financiador:
UNIVERSIDAD DE NAVARRA
Convocatoria:
2019 Convocatoria PIUNA
Fecha de inicio:
01/09/2018
Fecha fin:
31/08/2019
Importe concedido:
15.000,00€