43 research outputs found
Initial afferent lymphatic vessels controlling outbound leukocyte traffic from skin to lymph nodes
Tissue drains fluid and macromolecules through lymphatic vessels (LVs), which are lined by a specialized endothelium that expresses peculiar differentiation proteins, not found in blood vessels (i.e., LYVE-1, Podoplanin, PROX-1, and VEGFR-3). Lymphatic capillaries are characteristically devoid of a continuous basal membrane and are anchored to the ECM by elastic fibers that act as pulling ropes which open the vessel to avoid edema if tissue volume increases, as it occurs upon inflammation. LVs are also crucial for the transit of T lymphocytes and antigen presenting cells from tissue to draining lymph nodes (LN). Importantly, cell traffic control across lymphatic endothelium is differently regulated under resting and inflammatory conditions. Under steady-state non-inflammatory conditions, leukocytes enter into the lymphatic capillaries through basal membrane gaps (portals). This entrance is integrin-independent and seems to be mainly guided by CCL21 chemokine gradients acting on leukocytes expressing CCR7. In contrast, inflammatory processes in lymphatic capillaries involve a plethora of cytokines, chemokines, leukocyte integrins, and other adhesion molecules. Importantly, under inflammation a role for integrins and their ligands becomes apparent and, as a consequence, the number of leukocytes entering the lymphatic capillaries multiplies several-fold. Enhancing transmigration of dendritic cells en route to LN is conceivably useful for vaccination and cancer immunotherapy, whereas interference with such key mechanisms may ameliorate autoimmunity or excessive inflammation. Recent findings illustrate how, transient cell-to-cell interactions between lymphatic endothelial cells and leukocytes contribute to shape the subsequent behavior of leukocytes and condition the LV for subsequent trans-migratory events
New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis
CD137 (4-1BB) is a surface glycoprotein that belongs to the tumour necrosis factor receptor family (TNFRSF9). Its expression is induced on activation on a number of leucocyte types. Interestingly, for cancer immunotherapy, CD137 becomes expressed on primed T and natural killer (NK) cells, which on ligation provides powerful costimulatory signals. Perturbation of CD137 by CD137L or agonist monoclonal antibodies on activated CD8 T cells protects such antigen-specific cytotoxic T lymphocytes from apoptosis, enhances effector functionalities and favours persistence and memory differentiation. As a consequence, agonist antibodies exert potent antitumour effects in mouse models and the CD137 signalling domain is critical in chimeric antigen receptors (CAR) of CAR T cells approved to be used in the clinic. New formats of CD137 agonist moieties are being clinically developed, seeking potent costimulation targeted to the tumour microenvironment to avoid liver inflammation side effects, that have thus far limited and delayed clinical development
ICAM-1-LFA-1 dependent CD8+ T-Lymphocyte aggregation in tumor tissue prevents recirculation to draining lymph nodes
The quantity of T-lymphocytes reaching the draining lymph nodes from tumors is likely
important to mount effective distant responses and for the establishment of long term
systemic memory. Looking into mechanisms behind lymphocyte egress, we directed
our attention to leukocyte adhesion mechanisms inside tumors. Here we demonstrate
that activated T-cells form intra-tumor aggregates in a LFA-1-ICAM-1-dependent fashion
in mouse models of melanoma and breast cancer. We also provide evidence of the
presence of T-cell clusters in primary human melanoma. Disruption of LFA-1-ICAM-1
interactions, and thereby T-cell clustering, enhances the arrival of activated CD8+
T-cells to tumor draining lymph nodes in both transplanted and spontaneous cancer
models. Interestingly, upon ICAM-1 blockade, the expression of the chemotactic
receptor CCR7 augments in tumor infiltrating lymphocytes and in in-vitro de-clustered
T cells, as well as their ability to transmigrate across lymphatic endothelial cells. We
propose that ICAM-1-mediated homotypic T-lymphocyte aggregation may serve as a
tumor-mediated immune retention mechanism entrapping activated CD8+ T cells in
the tumor microenvironment. Modulation of T-cell adhesion may be of use to improve
the transit of activated lymphocytes toward the lymph nodes and their subsequent
recirculation
DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity
Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α–mediated CD8+-killing and immune-resistant lung tumors to anti–PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.This work was supported by Fundación para la investigación medica aplicada (FIMA), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC; CB16/12/00443), Spanish Association Against Cancer Scientific Foundation (AECC; GCB14-2170), Fundación Ramón Areces, Instituto de Salud Carlos III, and cofunded by the European Union (European Regional Development Fund, “A way to make Europe”; PI19/00098; PI19/00230; PI20/ 00419), Fundación Roberto Arnal Planelles, and International Association for the Study of Lung Cancer (IASLC) Fellowship funding (K. Valencia). M. Echepare was supported by Contratos Predoctorales de Formación en Investigación en Salud (PFIS), Instituto de Salud Carlos III, and co-funded by the European Union (European Social Fund, "Investing in your future"; FI20/00295)
Repurposing infectious disease vaccines for intratumoral immunotherapy
Intratumoral delivery of viruses and virus-associated molecular patterns can achieve antitumor effects that are largely mediated by the elicitation or potentiation of immune responses against the malignancy. Attenuated vaccines are approved and marketed as good manufactiring practice (GMP)-manufactured agents whose administration might be able to induce such effects. Recent reports in mouse transplantable tumor models indicate that the rotavirus, influenza and yellow fever vaccines can be especially suitable to elicit powerful antitumor immunity against cancer following intratumoral administration. These results highlight that intratumoral anti-infectious vaccines can turn cold tumors into hot, and underscore the key role played by virus-induced type I interferon pathways to overcome resistance to immune checkpoint-targeted antibodies
Mouse Models of Peritoneal Carcinomatosis to Develop Clinical Applications
Simple Summary Peritoneal carcinomatosis mouse models as a platform to test, improve and/or predict the appropriate therapeutic interventions in patients are crucial to providing medical advances. Here, we overview reported mouse models to explore peritoneal carcinomatosis in translational biomedical research. Peritoneal carcinomatosis of primary tumors originating in gastrointestinal (e.g., colorectal cancer, gastric cancer) or gynecologic (e.g., ovarian cancer) malignancies is a widespread type of tumor dissemination in the peritoneal cavity for which few therapeutic options are available. Therefore, reliable preclinical models are crucial for research and development of efficacious treatments for this condition. To date, a number of animal models have attempted to reproduce as accurately as possible the complexity of the tumor microenvironment of human peritoneal carcinomatosis. These include: Syngeneic tumor cell lines, human xenografts, patient-derived xenografts, genetically induced tumors, and 3D scaffold biomimetics. Each experimental model has its own strengths and limitations, all of which can influence the subsequent translational results concerning anticancer and immunomodulatory drugs under exploration. This review highlights the current status of peritoneal carcinomatosis mouse models for preclinical development of anticancer drugs or immunotherapeutic agents
Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL-8
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
The clinical application of cancer immunotherapy based on naturally circulating dendritic cells
Dendritic cells (DCs) can initiate and direct adaptive immune responses. This ability is exploitable in DC vaccination
strategies, in which DCs are educated ex vivo to present tumor antigens and are administered into the patient with
the aim to induce a tumor-specific immune response. DC vaccination remains a promising approach with the potential
to further improve cancer immunotherapy with little or no evidence of treatment-limiting toxicity. However, evidence
for objective clinical antitumor activity of DC vaccination is currently limited, hampering the clinical implementation.
One possible explanation for this is that the most commonly used monocyte-derived DCs may not be the best source
for DC-based immunotherapy. The novel approach to use naturally circulating DCs may be an attractive alternative. In
contrast to monocyte-derived DCs, naturally circulating DCs are relatively scarce but do not require extensive culture
periods. Thereby, their functional capabilities are preserved, the reproducibility of clinical applications is increased, and
the cells are not dysfunctional before injection. In human blood, at least three DC subsets can be distinguished,
plasmacytoid DCs, CD141+ and CD1c+ myeloid/conventional DCs, each with distinct functional characteristics. In
completed clinical trials, either CD1c+ myeloid DCs or plasmacytoid DCs were administered and showed encouraging
immunological and clinical outcomes. Currently, also the combination of CD1c+ myeloid and plasmacytoid DCs as well
as the intratumoral use of CD1c+ myeloid DCs is under investigation in the clinic. Isolation and culture strategies for
CD141+ myeloid DCs are being developed. Here, we summarize and discuss recent clinical developments and future
prospects of natural DC-based immunotherapy
Immunotherapeutic effects of intratumoral nanoplexed poly I:C
Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. BO-112 is a
nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing
immunogenic cell death features and which upon intratumoral release results in more prominent tumor infiltration
by T lymphocytes. Intratumoral treatment with BO-112 of subcutaneous tumors derived from MC38, 4 T1 and B16-
F10 leads to remarkable local disease control dependent on type-1 interferon and gamma-interferon. Some degree
of control of non-injected tumor lesions following BO-112 intratumoral treatment was found in mice bearing bilateral
B16-OVA melanomas, an activity which was enhanced with co-treatment with systemic anti-CD137 and anti-PD-L1
mAbs. More abundant CD8+ T lymphocytes were found in B16-OVA tumor-draining lymph nodes and in the tumor
microenvironment following intratumoral BO-112 treatment, with enhanced numbers of tumor antigen-specific
cytotoxic T lymphocytes. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a
marked upregulation of the type-I interferon pathway. Inspired by these data, intratumorally delivered BO-112 is
being tested in cancer patients (NCT02828098)
Campus de Segovia, Universidad de Valladolid [Hojas Resumen]
Campus de Segovia, Universidad de Valladoli