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David Escors

Navarrabiomed-FMS, Oncology, Principal Investigator

University College London, Division of infection and Immunity, Honorory research fellow

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In our research group we are focused on discovering novel molecular and cellular mechanisms of antigen recognition by the immune system. Our ultimate goal is to cure cancer by immunotherapy using genetic vaccination.

To achieve this, we use gene therapy approaches to modulate the function of myeloid dendritic cells, with the aim of enhancing anti-cancer T and B cell responses.

Current PhD researchers in our group:

* Mehdi Baratchian (2010-2013): Mechanisms of NF-kB activation by cellular and viral oncoproteins

* Christopher Bricogne (January 2012-): Mechanisms of PD-L1/PD-1-induced T cell receptor down-modulation.

* Alessio Lanna (September 2011-): T cell senescence

* Therese Liechtenstein (September 2012-): Modulation of co-stimulation to enhance tumour immunotherapy
Address: Navarrabiomed-FMS
C/Irunlarrea 3
31008
Pamplona, Navarra
Spain

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Papers by David Escors

Highly differentiated CD4 T cells Unequivocally Identify Primary Resistance and Risk of Hyperprogression to PD-L1/PD-1 Immune Checkpoint Blockade in Lung Cancer

bioRxiv (Cold Spring Harbor Laboratory), May 11, 2018

The majority of lung cancer patients are refractory to PD-L1/PD-1 blockade monotherapy. This ther... more The majority of lung cancer patients are refractory to PD-L1/PD-1 blockade monotherapy. This therapy may even accelerate progression and death in a group of patients called hyperprogressors. Here we demonstrate that the efficacy of PD-L1/PD-1 blockade therapy relies on baseline circulating highly-differentiated CD28-CD27-CD4 T cells (THD cells), which segregate patients in two non-overlapping groups. THD cells in cancer patients mostly comprised of central memory subsets that potently coupregulated PD-1 and LAG3 upon antigen recognition. Low baseline THD numbers unequivocally identified intrinsic non-responders and hyperprogressors, whom aberrantly responded to therapy with a potent systemic proliferative THD cell burst. Responder patients showed significant reductions in systemic CD4 THD cells throughout therapy linked to expansion of the CD28+ CD27+ CD4 T cell compartment. Quantification of THD cells from peripheral blood samples prior to therapy allows identification of non-responders, hyperprogressors and responders, a critical issue in clinical oncology. These results place CD4 T cell responses at the center of anti-tumor immunity.

PD-1/LAG-3 Dysfunctionality Signatures in Human Cancers

ABSTRACTA significant number of cancer patients do not benefit from PD-L1/PD-1 blockade immunothe... more ABSTRACTA significant number of cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD- 1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers with high T-cell infiltration. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic and epigenetic pathways. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. These results uncovered distinct degrees of T-cell dysfunctionality. Global changes were cross-evaluated among T- cell lines with multiomic biopsy data to identify genetic, metabolic, and proteomic programmes regulated by PD-1/LAG-3 dysfunctionality. One of these relied on differential regulation of E3 ubiquitin ligase...

OP05 Proteomic footprint of murine tumor-associated myeloid populations for myeloid cell reprogramming in cancer

ESMO open, Dec 1, 2022

Correspondence to

involvement of RASSF2 hypermethylation in breast

Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis

Cancer Letters, 2021

Myeloid-derived suppressor cells (MDSCs) play a major role in cancer progression. In this study, ... more Myeloid-derived suppressor cells (MDSCs) play a major role in cancer progression. In this study, we investigated the mechanisms by which complement C5a increases the capacity of polymorphonuclear MDSCs (PMN-MDSCs) to promote tumor growth and metastatic spread. Stimulation of PMN-MDSCs with C5a favored the invasion of cancer cells via a process dependent on the formation of neutrophil extracellular traps (NETs). NETosis was dependent on the production of high mobility group box 1 (HMGB1) by cancer cells. Moreover, C5a induced the surface expression of the HMGB1 receptors TLR4 and RAGE in PMN-MDSCs. In a mouse lung metastasis model, inhibition of C5a, C5a receptor-1 (C5aR1) or NETosis reduced the number of circulating-tumor cells (CTCs) and the metastatic burden. In support of the translational relevance of these findings, C5a was able to stimulate migration and NETosis in PMN-MDSCs obtained from lung cancer patients. Furthermore, myeloperoxidase (MPO)-DNA complexes, as markers of NETosis, were elevated in lung cancer patients and significantly correlated with C5a levels. In conclusion, C5a induces the formation of NETs from PMN-MDSCs in the presence of cancer cells, which may facilitate cancer cell dissemination and metastasis.

Myeloid-Derived Suppressor Cells and Cancer

SpringerBriefs in Immunology, 2016

The book starts with an introduction to and history of myeloid-derived suppressor cells (MDSCs), ... more The book starts with an introduction to and history of myeloid-derived suppressor cells (MDSCs), followed by a description of their differentiation, their role in the tumour microenvironment and their therapeutic targeting. It closes with an outlook on future developments. In cancer patients, myelopoiesis is perturbed and instead of generating immunogenic myeloid cells (such as dendritic cells, inflammatory macrophages and granulocytes), there is an increase in highly immature MDSCs. These cells are distributed systemically, resulting in general immunosuppression. They also infiltrate tumours, promoting their progression and metastasis by inhibiting the natural anti-tumour immune response. As these cells also interact with classical anti-neoplastic treatments, they have become major therapeutic targets in the pharmaceutical industry and in oncology research

Cancer Immunotherapy of TLR4 Agonist–Antigen Constructs Enhanced with Pathogen‐Mimicking Magnetite Nanoparticles and Checkpoint Blockade of PD‐L1

Small, 2018

Despite the tremendous potential of Toll‐like receptor 4 (TLR4) agonists in vaccines, their effic... more Despite the tremendous potential of Toll‐like receptor 4 (TLR4) agonists in vaccines, their efficacy as monotherapy to treat cancer has been limited. Only some lipopolysaccharides (LPS) isolated from particular bacterial strains or structures like monophosphoryl lipid A (MPLA) derived from lipooligosaccharide (LOS), avoid toxic overactivation of innate immune responses while retaining adequate immunogenicity to act as adjuvants. Here, different LOS structures are incorporated into nanoparticle‐filled phospholipid micelles for efficient vaccine delivery and more potent cancer immunotherapy. The structurally unique LOS of the plant pathogen Xcc is incorporated into phospholipid micelles encapsulating iron oxide nanoparticles, producing stable pathogen‐mimicking nanostructures suitable for targeting antigen presenting cells in the lymph nodes. The antigen is conjugated via a hydrazone bond, enabling rapid, easy‐to‐monitor and high‐yield antigen ligation at low concentrations. The prote...

Constraints on General Relativity Geodesics by a Covariant Geometric Uncertainty Principle

General relativity is a theory for gravitation based on Riemannian geometry, difficult to compati... more General relativity is a theory for gravitation based on Riemannian geometry, difficult to compatibilize with quantum mechanics. This is evident in relativistic problems in which quantum effects cannot be discarded. For example in quantum gravity, gravitation of zero-point energy or events close to a black hole singularity. Here, we set up a mathematical model to select general relativity geodesics according to compatibility with the uncertainty principle. To achieve this, we derived a geometric expression of the uncertainty principle (GeUP). This formulation identified proper space-time length with Planck length by a geodesic-derived scalar. GeUP imposed a minimum allowed value for the interval of proper space-time which depended on the particular space-time geometry. GeUP forced the introduction of a “zero-point” curvature perturbation over flat Minkowski space, caused exclusively by quantum uncertainty but not to gravitation. When applied to the Schwarzschild metric and choosing r...

Systemic CD4 immunity: A powerful clinical biomarker for PD‐L1/PD‐1 immunotherapy

EMBO Molecular Medicine, 2020

Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics

Cancers, 2020

Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an accelerati... more Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly...

Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses

Molecular Therapy, 2019

Characterization of Macrophage Endogenous S-Nitrosoproteome Using a Cysteine-Specific Phosphonate Adaptable Tag in Combination with TiO2 Chromatography

Journal of Proteome Research, 2018

Perforin and Granzyme B Expressed by Murine Myeloid-Derived Suppressor Cells: A Study on Their Role in Outgrowth of Cancer Cells

Cancers, 2019

A wide-range of myeloid-derived suppressor cell (MDSC)-mediated immune suppressive functions has ... more A wide-range of myeloid-derived suppressor cell (MDSC)-mediated immune suppressive functions has previously been described. Nevertheless, potential novel mechanisms by which MDSCs aid tumor progression are, in all likelihood, still unrecognized. Next to its well-known expression in natural killer cells and cytotoxic T lymphocytes (CTLs), granzyme B (GzmB) expression has been found in different cell types. In an MDSC culture model, we demonstrated perforin and GzmB expression. Furthermore, similar observations were made in MDSCs isolated from tumor-bearing mice. Even in MDSCs from humans, GzmB expression was demonstrated. Of note, B16F10 melanoma cells co-cultured with perforin/GzmB knock out mice (KO) MDSCs displayed a remarkable decrease in invasive potential. B16F10 melanoma cells co-injected with KO MDSCs, displayed a significant slower growth curve compared to tumor cells co-injected with wild type (WT) MDSCs. In vivo absence of perforin/GzmB in MDSCs resulted in a higher number...

Functional systemic CD 4 immunity is required for clinical responses to PD ‐L1/ PD ‐1 blockade therapy

EMBO Molecular Medicine, 2019

The majority of lung cancer patients progressing from conventional therapies are refractory to PD... more The majority of lung cancer patients progressing from conventional therapies are refractory to PD-L1/PD-1 blockade monotherapy. Here we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients CD4 T cells possessed significant proliferative capacities, low co-expression of PD-1/LAG-3 and were responsive to PD-1 blockade ex vivo and in vivo. In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer-specific CD4 and CD8 T cells. CD4 T cells in these patients proliferated very poorly, strongly co-upregulated PD-1/LAG-3, and were largely refractory to PD-1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T cell dysfunctionality was caused by PD-1/LAG-3 coexpression, and could be reverted by co-blockade. Patients with functional CD4 immunity and PD-L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD-L1/PD-1 blockade therapy.

Myeloid-derived suppressor cells and their "inconvenient" plasticity

Journal of Immunological Sciences, 2018

Myeloid-derived suppressor cells (MDSCs) comprise certain types of myeloid subsets with strong im... more Myeloid-derived suppressor cells (MDSCs) comprise certain types of myeloid subsets with strong immunosuppressive activities, which expand at high levels in pathological conditions such as cancer. A major drawback in the study of MDSCs is the extraordinary plasticity of the myeloid lineage that hampers the identification of MDSC subsets, especially in humans. Here we provide a brief overview on MDSCs, their differentiation and the current difficulties in classifying these immunosuppressive subsets.

PD-L1 Expression in Systemic Immune Cell Populations as a Potential Predictive Biomarker of Responses to PD-L1/PD-1 Blockade Therapy in Lung Cancer

International Journal of Molecular Sciences, 2019

PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blocka... more PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blockade anticancer therapies, particularly for lung cancer. However, the reliability of this marker is still under debate. Moreover, PD-L1 is widely expressed by many immune cell types, and little is known on the relevance of systemic PD-L1+ cells for responses to immune checkpoint blockade. We present two clinical cases of patients with non-small cell lung cancer (NSCLC) and PD-L1-negative tumors treated with atezolizumab that showed either objective responses or progression. These patients showed major differences in the distribution of PD-L1 expression within systemic immune cells. Based on these results, an exploratory study was carried out with 32 cases of NSCLC patients undergoing PD-L1/PD-1 blockade therapies, to compare PD-L1 expression profiles and their relationships with clinical outcomes. Significant differences in the percentage of PD-L1+ CD11b+ myeloid cell populations were foun...

The intracellular signalosome of PD-L1 in cancer cells

Signal Transduction and Targeted Therapy, 2018

Programmed cell death-1 ligand-1 (PD-L1) overexpression in cancer cells accelerates tumor progres... more Programmed cell death-1 ligand-1 (PD-L1) overexpression in cancer cells accelerates tumor progression. PD-L1 possesses two main pro-oncogenic functions. First, PD-L1 is a strong immunosuppressive molecule that inactivates tumor-specific T cells by binding to the inhibitory receptor PD-1. Second, PD-L1 function relies on the delivery of intrinsic intracellular signals that enhance cancer cell survival, regulate stress responses and confer resistance toward pro-apoptotic stimuli, such as interferons. Here, we review the current knowledge on intracellular signal transduction pathways regulated by PD-L1, describe its associated signalosome and discuss potential combinations of targeted therapies against the signalosome with PD-L1/PD-1 blockade therapies.

PD1 signal transduction pathways in T cells

Oncotarget, 2017

The use of immune checkpoint inhibitors for the treatment of cancer is revolutionizing oncology. ... more The use of immune checkpoint inhibitors for the treatment of cancer is revolutionizing oncology. Amongst these therapeutic agents, antibodies that block PD-L1/PD1 interactions between cancer cells and T cells are demonstrating high efficacies and low toxicities. Despite all the recent advances, very little is yet known on the molecular intracellular signaling pathways regulated by either PD-L1 or PD1. Here we review the current knowledge on PD1-dependent intracellular signaling pathways, and the consequences of disrupting PD1 signal transduction.

Non-invasive assessment of murine PD-L1 levels in syngeneic tumor models by nuclear imaging with nanobody tracers

Oncotarget, 2017

Blockade of the inhibitory PD-1/PD-L1 immune checkpoint axis is a promising cancer treatment. Non... more Blockade of the inhibitory PD-1/PD-L1 immune checkpoint axis is a promising cancer treatment. Nonetheless, a significant number of patients and malignancies do not respond to this therapy. To develop a screen for response to PD-1/PD-L1 inhibition, it is critical to develop a non-invasive tool to accurately assess dynamic immune checkpoint expression. Here we evaluated non-invasive SPECT/CT imaging of PD-L1 expression, in murine tumor models with varying PD-L1 expression, using high affinity PD-L1-specific nanobodies (Nbs). We generated and characterized 37 Nbs recognizing mouse PD-L1. Among those, four Nbs C3, C7, E2 and E4 were selected and evaluated for preclinical imaging of PD-L1 in syngeneic mice. We performed SPECT/CT imaging in wild type versus PD-L1 knockout mice, using Technetium-99m (99m Tc) labeled Nbs. Nb C3 and E2 showed specific antigen binding and beneficial biodistribution. Through the use of CRISPR/Cas9 PD-L1 knockout TC-1 lung epithelial cell lines, we demonstrate that SPECT/CT imaging using Nb C3 and E2 identifies PD-L1 expressing tumors, but not PD-L1 non-expressing tumors, thereby confirming the diagnostic potential of the selected Nbs. In conclusion, these data show that Nbs C3 and E2 can be used to noninvasively image PD-L1 levels in the tumor, with the strength of the signal correlating with PD-L1 levels. These findings warrant further research into the use of Nbs as a tool to image inhibitory signals in the tumor environment.

Dendritic Cells Cross-Present Immunogenic Lentivector-Encoded Antigen from Transduced Cells to Prime Functional T Cell Immunity

Molecular therapy : the journal of the American Society of Gene Therapy, Feb 1, 2017

Recombinant lentiviral vectors (LVs) are highly effective vaccination vehicles that elicit protec... more Recombinant lentiviral vectors (LVs) are highly effective vaccination vehicles that elicit protective T cell immunity in disease models. Dendritic cells (DCs) acquire antigen at sites of vaccination and migrate to draining lymph nodes, where they prime vaccine-specific T cells. The potency with which LVs activate CD8(+) T cell immunity has been attributed to the transduction of DCs at the immunization site and durable presentation of LV-encoded antigens. However, it is not known how LV-encoded antigens continue to be presented to T cells once directly transduced DCs have turned over. Here, we report that LV-encoded antigen is efficiently cross-presented by DCs in vitro. We have further exploited the temporal depletion of DCs in the murine CD11c.DTR (diphtheria toxin receptor) model to demonstrate that repopulating DCs that were absent at the time of immunization cross-present LV-encoded antigen to T cells in vivo. Indirect presentation of antigen from transduced cells by DCs is suff...

Highly differentiated CD4 T cells Unequivocally Identify Primary Resistance and Risk of Hyperprogression to PD-L1/PD-1 Immune Checkpoint Blockade in Lung Cancer

bioRxiv (Cold Spring Harbor Laboratory), May 11, 2018

The majority of lung cancer patients are refractory to PD-L1/PD-1 blockade monotherapy. This ther... more The majority of lung cancer patients are refractory to PD-L1/PD-1 blockade monotherapy. This therapy may even accelerate progression and death in a group of patients called hyperprogressors. Here we demonstrate that the efficacy of PD-L1/PD-1 blockade therapy relies on baseline circulating highly-differentiated CD28-CD27-CD4 T cells (THD cells), which segregate patients in two non-overlapping groups. THD cells in cancer patients mostly comprised of central memory subsets that potently coupregulated PD-1 and LAG3 upon antigen recognition. Low baseline THD numbers unequivocally identified intrinsic non-responders and hyperprogressors, whom aberrantly responded to therapy with a potent systemic proliferative THD cell burst. Responder patients showed significant reductions in systemic CD4 THD cells throughout therapy linked to expansion of the CD28+ CD27+ CD4 T cell compartment. Quantification of THD cells from peripheral blood samples prior to therapy allows identification of non-responders, hyperprogressors and responders, a critical issue in clinical oncology. These results place CD4 T cell responses at the center of anti-tumor immunity.

PD-1/LAG-3 Dysfunctionality Signatures in Human Cancers

ABSTRACTA significant number of cancer patients do not benefit from PD-L1/PD-1 blockade immunothe... more ABSTRACTA significant number of cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD- 1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers with high T-cell infiltration. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic and epigenetic pathways. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. These results uncovered distinct degrees of T-cell dysfunctionality. Global changes were cross-evaluated among T- cell lines with multiomic biopsy data to identify genetic, metabolic, and proteomic programmes regulated by PD-1/LAG-3 dysfunctionality. One of these relied on differential regulation of E3 ubiquitin ligase...

OP05 Proteomic footprint of murine tumor-associated myeloid populations for myeloid cell reprogramming in cancer

ESMO open, Dec 1, 2022

Correspondence to

involvement of RASSF2 hypermethylation in breast

Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis

Cancer Letters, 2021

Myeloid-derived suppressor cells (MDSCs) play a major role in cancer progression. In this study, ... more Myeloid-derived suppressor cells (MDSCs) play a major role in cancer progression. In this study, we investigated the mechanisms by which complement C5a increases the capacity of polymorphonuclear MDSCs (PMN-MDSCs) to promote tumor growth and metastatic spread. Stimulation of PMN-MDSCs with C5a favored the invasion of cancer cells via a process dependent on the formation of neutrophil extracellular traps (NETs). NETosis was dependent on the production of high mobility group box 1 (HMGB1) by cancer cells. Moreover, C5a induced the surface expression of the HMGB1 receptors TLR4 and RAGE in PMN-MDSCs. In a mouse lung metastasis model, inhibition of C5a, C5a receptor-1 (C5aR1) or NETosis reduced the number of circulating-tumor cells (CTCs) and the metastatic burden. In support of the translational relevance of these findings, C5a was able to stimulate migration and NETosis in PMN-MDSCs obtained from lung cancer patients. Furthermore, myeloperoxidase (MPO)-DNA complexes, as markers of NETosis, were elevated in lung cancer patients and significantly correlated with C5a levels. In conclusion, C5a induces the formation of NETs from PMN-MDSCs in the presence of cancer cells, which may facilitate cancer cell dissemination and metastasis.

Myeloid-Derived Suppressor Cells and Cancer

SpringerBriefs in Immunology, 2016

The book starts with an introduction to and history of myeloid-derived suppressor cells (MDSCs), ... more The book starts with an introduction to and history of myeloid-derived suppressor cells (MDSCs), followed by a description of their differentiation, their role in the tumour microenvironment and their therapeutic targeting. It closes with an outlook on future developments. In cancer patients, myelopoiesis is perturbed and instead of generating immunogenic myeloid cells (such as dendritic cells, inflammatory macrophages and granulocytes), there is an increase in highly immature MDSCs. These cells are distributed systemically, resulting in general immunosuppression. They also infiltrate tumours, promoting their progression and metastasis by inhibiting the natural anti-tumour immune response. As these cells also interact with classical anti-neoplastic treatments, they have become major therapeutic targets in the pharmaceutical industry and in oncology research

Cancer Immunotherapy of TLR4 Agonist–Antigen Constructs Enhanced with Pathogen‐Mimicking Magnetite Nanoparticles and Checkpoint Blockade of PD‐L1

Small, 2018

Despite the tremendous potential of Toll‐like receptor 4 (TLR4) agonists in vaccines, their effic... more Despite the tremendous potential of Toll‐like receptor 4 (TLR4) agonists in vaccines, their efficacy as monotherapy to treat cancer has been limited. Only some lipopolysaccharides (LPS) isolated from particular bacterial strains or structures like monophosphoryl lipid A (MPLA) derived from lipooligosaccharide (LOS), avoid toxic overactivation of innate immune responses while retaining adequate immunogenicity to act as adjuvants. Here, different LOS structures are incorporated into nanoparticle‐filled phospholipid micelles for efficient vaccine delivery and more potent cancer immunotherapy. The structurally unique LOS of the plant pathogen Xcc is incorporated into phospholipid micelles encapsulating iron oxide nanoparticles, producing stable pathogen‐mimicking nanostructures suitable for targeting antigen presenting cells in the lymph nodes. The antigen is conjugated via a hydrazone bond, enabling rapid, easy‐to‐monitor and high‐yield antigen ligation at low concentrations. The prote...

Constraints on General Relativity Geodesics by a Covariant Geometric Uncertainty Principle

General relativity is a theory for gravitation based on Riemannian geometry, difficult to compati... more General relativity is a theory for gravitation based on Riemannian geometry, difficult to compatibilize with quantum mechanics. This is evident in relativistic problems in which quantum effects cannot be discarded. For example in quantum gravity, gravitation of zero-point energy or events close to a black hole singularity. Here, we set up a mathematical model to select general relativity geodesics according to compatibility with the uncertainty principle. To achieve this, we derived a geometric expression of the uncertainty principle (GeUP). This formulation identified proper space-time length with Planck length by a geodesic-derived scalar. GeUP imposed a minimum allowed value for the interval of proper space-time which depended on the particular space-time geometry. GeUP forced the introduction of a “zero-point” curvature perturbation over flat Minkowski space, caused exclusively by quantum uncertainty but not to gravitation. When applied to the Schwarzschild metric and choosing r...

Systemic CD4 immunity: A powerful clinical biomarker for PD‐L1/PD‐1 immunotherapy

EMBO Molecular Medicine, 2020

Early Detection of Hyperprogressive Disease in Non-Small Cell Lung Cancer by Monitoring of Systemic T Cell Dynamics

Cancers, 2020

Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an accelerati... more Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28− CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly...

Short-Term Local Expression of a PD-L1 Blocking Antibody from a Self-Replicating RNA Vector Induces Potent Antitumor Responses

Molecular Therapy, 2019

Characterization of Macrophage Endogenous S-Nitrosoproteome Using a Cysteine-Specific Phosphonate Adaptable Tag in Combination with TiO2 Chromatography

Journal of Proteome Research, 2018

Perforin and Granzyme B Expressed by Murine Myeloid-Derived Suppressor Cells: A Study on Their Role in Outgrowth of Cancer Cells

Cancers, 2019

A wide-range of myeloid-derived suppressor cell (MDSC)-mediated immune suppressive functions has ... more A wide-range of myeloid-derived suppressor cell (MDSC)-mediated immune suppressive functions has previously been described. Nevertheless, potential novel mechanisms by which MDSCs aid tumor progression are, in all likelihood, still unrecognized. Next to its well-known expression in natural killer cells and cytotoxic T lymphocytes (CTLs), granzyme B (GzmB) expression has been found in different cell types. In an MDSC culture model, we demonstrated perforin and GzmB expression. Furthermore, similar observations were made in MDSCs isolated from tumor-bearing mice. Even in MDSCs from humans, GzmB expression was demonstrated. Of note, B16F10 melanoma cells co-cultured with perforin/GzmB knock out mice (KO) MDSCs displayed a remarkable decrease in invasive potential. B16F10 melanoma cells co-injected with KO MDSCs, displayed a significant slower growth curve compared to tumor cells co-injected with wild type (WT) MDSCs. In vivo absence of perforin/GzmB in MDSCs resulted in a higher number...

Functional systemic CD 4 immunity is required for clinical responses to PD ‐L1/ PD ‐1 blockade therapy

EMBO Molecular Medicine, 2019

The majority of lung cancer patients progressing from conventional therapies are refractory to PD... more The majority of lung cancer patients progressing from conventional therapies are refractory to PD-L1/PD-1 blockade monotherapy. Here we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients CD4 T cells possessed significant proliferative capacities, low co-expression of PD-1/LAG-3 and were responsive to PD-1 blockade ex vivo and in vivo. In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer-specific CD4 and CD8 T cells. CD4 T cells in these patients proliferated very poorly, strongly co-upregulated PD-1/LAG-3, and were largely refractory to PD-1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T cell dysfunctionality was caused by PD-1/LAG-3 coexpression, and could be reverted by co-blockade. Patients with functional CD4 immunity and PD-L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD-L1/PD-1 blockade therapy.

Myeloid-derived suppressor cells and their "inconvenient" plasticity

Journal of Immunological Sciences, 2018

Myeloid-derived suppressor cells (MDSCs) comprise certain types of myeloid subsets with strong im... more Myeloid-derived suppressor cells (MDSCs) comprise certain types of myeloid subsets with strong immunosuppressive activities, which expand at high levels in pathological conditions such as cancer. A major drawback in the study of MDSCs is the extraordinary plasticity of the myeloid lineage that hampers the identification of MDSC subsets, especially in humans. Here we provide a brief overview on MDSCs, their differentiation and the current difficulties in classifying these immunosuppressive subsets.

PD-L1 Expression in Systemic Immune Cell Populations as a Potential Predictive Biomarker of Responses to PD-L1/PD-1 Blockade Therapy in Lung Cancer

International Journal of Molecular Sciences, 2019

PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blocka... more PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blockade anticancer therapies, particularly for lung cancer. However, the reliability of this marker is still under debate. Moreover, PD-L1 is widely expressed by many immune cell types, and little is known on the relevance of systemic PD-L1+ cells for responses to immune checkpoint blockade. We present two clinical cases of patients with non-small cell lung cancer (NSCLC) and PD-L1-negative tumors treated with atezolizumab that showed either objective responses or progression. These patients showed major differences in the distribution of PD-L1 expression within systemic immune cells. Based on these results, an exploratory study was carried out with 32 cases of NSCLC patients undergoing PD-L1/PD-1 blockade therapies, to compare PD-L1 expression profiles and their relationships with clinical outcomes. Significant differences in the percentage of PD-L1+ CD11b+ myeloid cell populations were foun...

The intracellular signalosome of PD-L1 in cancer cells

Signal Transduction and Targeted Therapy, 2018

Programmed cell death-1 ligand-1 (PD-L1) overexpression in cancer cells accelerates tumor progres... more Programmed cell death-1 ligand-1 (PD-L1) overexpression in cancer cells accelerates tumor progression. PD-L1 possesses two main pro-oncogenic functions. First, PD-L1 is a strong immunosuppressive molecule that inactivates tumor-specific T cells by binding to the inhibitory receptor PD-1. Second, PD-L1 function relies on the delivery of intrinsic intracellular signals that enhance cancer cell survival, regulate stress responses and confer resistance toward pro-apoptotic stimuli, such as interferons. Here, we review the current knowledge on intracellular signal transduction pathways regulated by PD-L1, describe its associated signalosome and discuss potential combinations of targeted therapies against the signalosome with PD-L1/PD-1 blockade therapies.

PD1 signal transduction pathways in T cells

Oncotarget, 2017

The use of immune checkpoint inhibitors for the treatment of cancer is revolutionizing oncology. ... more The use of immune checkpoint inhibitors for the treatment of cancer is revolutionizing oncology. Amongst these therapeutic agents, antibodies that block PD-L1/PD1 interactions between cancer cells and T cells are demonstrating high efficacies and low toxicities. Despite all the recent advances, very little is yet known on the molecular intracellular signaling pathways regulated by either PD-L1 or PD1. Here we review the current knowledge on PD1-dependent intracellular signaling pathways, and the consequences of disrupting PD1 signal transduction.

Non-invasive assessment of murine PD-L1 levels in syngeneic tumor models by nuclear imaging with nanobody tracers

Oncotarget, 2017

Blockade of the inhibitory PD-1/PD-L1 immune checkpoint axis is a promising cancer treatment. Non... more Blockade of the inhibitory PD-1/PD-L1 immune checkpoint axis is a promising cancer treatment. Nonetheless, a significant number of patients and malignancies do not respond to this therapy. To develop a screen for response to PD-1/PD-L1 inhibition, it is critical to develop a non-invasive tool to accurately assess dynamic immune checkpoint expression. Here we evaluated non-invasive SPECT/CT imaging of PD-L1 expression, in murine tumor models with varying PD-L1 expression, using high affinity PD-L1-specific nanobodies (Nbs). We generated and characterized 37 Nbs recognizing mouse PD-L1. Among those, four Nbs C3, C7, E2 and E4 were selected and evaluated for preclinical imaging of PD-L1 in syngeneic mice. We performed SPECT/CT imaging in wild type versus PD-L1 knockout mice, using Technetium-99m (99m Tc) labeled Nbs. Nb C3 and E2 showed specific antigen binding and beneficial biodistribution. Through the use of CRISPR/Cas9 PD-L1 knockout TC-1 lung epithelial cell lines, we demonstrate that SPECT/CT imaging using Nb C3 and E2 identifies PD-L1 expressing tumors, but not PD-L1 non-expressing tumors, thereby confirming the diagnostic potential of the selected Nbs. In conclusion, these data show that Nbs C3 and E2 can be used to noninvasively image PD-L1 levels in the tumor, with the strength of the signal correlating with PD-L1 levels. These findings warrant further research into the use of Nbs as a tool to image inhibitory signals in the tumor environment.

Dendritic Cells Cross-Present Immunogenic Lentivector-Encoded Antigen from Transduced Cells to Prime Functional T Cell Immunity

Molecular therapy : the journal of the American Society of Gene Therapy, Feb 1, 2017

Recombinant lentiviral vectors (LVs) are highly effective vaccination vehicles that elicit protec... more Recombinant lentiviral vectors (LVs) are highly effective vaccination vehicles that elicit protective T cell immunity in disease models. Dendritic cells (DCs) acquire antigen at sites of vaccination and migrate to draining lymph nodes, where they prime vaccine-specific T cells. The potency with which LVs activate CD8(+) T cell immunity has been attributed to the transduction of DCs at the immunization site and durable presentation of LV-encoded antigens. However, it is not known how LV-encoded antigens continue to be presented to T cells once directly transduced DCs have turned over. Here, we report that LV-encoded antigen is efficiently cross-presented by DCs in vitro. We have further exploited the temporal depletion of DCs in the murine CD11c.DTR (diphtheria toxin receptor) model to demonstrate that repopulating DCs that were absent at the time of immunization cross-present LV-encoded antigen to T cells in vivo. Indirect presentation of antigen from transduced cells by DCs is suff...

Constraints on General Relativity Geodesics by a Covariant Geometric Uncertainty Principle

Preprints, 2021

The classical uncertainty principle inequalities were imposed as a mathematical constraint over t... more The classical uncertainty principle inequalities were imposed as a mathematical constraint over the general relativity geodesic equation. In this way, the uncertainty principle was reformulated in terms of the proper space-time length element, Planck length and a geodesic-derived scalar, leading to a geometric expression for the uncertainty principle (GeUP). This re-formulation confirmed the necessity for a minimum length for the space-time line element in the geodesic, dependent on a geodesic-derived scalar which made the expression Lorentz-covariant. In agreement with quantum gravity theories, GeUP required the imposition of a perturbation over the background Minkowski metric unrelated to classical gravity. When applied to the Schwarzschild metric, a geodesic exclusion zone was found around the singularity where uncertainty in space-time diverged to infinity.

Direct derivation of Minkowski space and special relativity from an invariant tensor statement and a condition of simultaneity for the null 4-vector. Solutions for time-like and space-like trajectories

Preprint, 2021

Derivation of special relativity classically relies on the use of inertial reference frames separ... more Derivation of special relativity classically relies on the use of inertial reference frames separat-ing at a constant velocity, combined with the constancy of the speed of light as a founding defi-nition of simultaneity. Einstein´s original method for derivation provides the general frame-work in which special relativity is often taught. While this approach is intuitive for students, it is nevertheless confusing in some aspects and lacks clarity in certain steps. Hence, special relativity is very often questioned with paradoxes and apparent mathematical inconsistencies. In most in-stances, these paradoxes are set up under improper mathematical frameworks, or in systems which are not invariant under coordinate transformations. Here, Minskowski space and special relativity are fully derived from an invariant tensor statement valid in any reference frame, with the simultaneity condition imposed on the 4-dimensional null vector. This approach derives Minkowski space with a very limited number of steps in tensor space without the need of in-troducing separating inertial reference frames. From it, the main features of special relativity for bradyon and tachyon trajectories are derived. This solution is particularly adequate for students of special and general relativity, as it is simple, straightforward and mathematically consistent.

Senescent CD4 T cells unequivocally identify primary resistance and risk of hyperprogression to PD-L1/PD-1 immune checkpoint blockade in lung cancer