Valeriya Kuznetsova

University of Alabama at Birmingham

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Robert S. Welner

University of Alabama at Birmingham

Sweta B. Patel

University of Alabama at Birmingham

Paran Goel

University of Alabama at Birmingham

Alana Franceski

University of Alabama at Birmingham

Victoria Matkins

University of Alabama at Birmingham

Ashley N. Connelly

University of Alabama at Birmingham

Amanda Costa

University of Alabama at Birmingham

Virginia Camacho

Harvard University

Sergey V. Kulemzin

Siberian Branch of the Russian Academy of Sciences

Francesca Luca

Wayne State University

Cooperative Institutions

University of Alabama at Birmingham

Universidade de São Paulo

Harvard University

University of Alabama

Clinics Hospital of Ribeirão Preto

Russian Academy of Sciences

Emory University

University of Colorado Denver

Siberian Branch of the Russian Academy of Sciences

Beth Israel Deaconess Medical Center

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

HIV-1 infection is associated with increased prevalence of immature neutrophils and alterations in total neutrophil phenotype and metabolic profile

The Journal of Immunology (2020)

Ashley N. Connelly Harish C. Pal Marcus D. Davis Krystle L. Ong Valeriya Kuznetsova

Abstract Despite successful viral control, HIV-1-infected individuals have a higher risk of developing life-threatening comorbidities including liver and cardiovascular diseases which are associated with inflammation and immune dysregulation. However, the specific mediators driving these pathologies are not yet understood. Neutrophils are increasingly recognized as a heterogeneous population with critical roles in immune regulation and disease pathogenesis. Methods of neutrophil characterization developed in our laboratory have facilitated the identification of novel neutrophil subpopulations including two subsets of low-density neutrophils (LDNs). LDNs are known to be expanded in inflammatory conditions including cancers and chronic infections. The LDN subpopulations identified in our laboratory represent different maturation states as indicated by their distinct nuclear morphologies and phenotypic differences [mature (mLDNs) CD16+CD64Low and immature (imLNDs) CD16−CD64+]. Our findings indicate that imLDNs have a reduced capacity for reactive oxygen species production and phagocytosis. We present data demonstrating that HIV-1/AIDS is associated with a higher frequency of imLDNs and significant alterations in total neutrophil phenotype (decreased CD16 and increased CXCR4 and CD10), function, and metabolism including increased expression of genes related to oxidative phosphorylation and mTOR signaling. Observed changes in neutrophil populations correlate with key clinical parameters including CD4+ T cell count, level of liver fibrosis, and arterial stiffness suggesting an important role for these cells and specific subsets in the pathogenesis of HIV-1/AIDS and potentially other inflammatory diseases.

CD16

CD64

Pathogenesis

Immune Dysregulation

10.4049/jimmunol.204.supp.225.32

Cite

Citations (0)

Leukemic Cytokines co-opt Regulatory T cell and Th17 immunity to promote chronic myeloid leukemia

The Journal of Immunology (2021)

Virginia Camacho Victoria Matkins Sweta B. Patel Valeriya Kuznetsova Ashlyn E Anderson

Abstract Non-immune roles of Regulatory T cells (Tregs) have been described across various tissues. However, the mechanisms by which T cells regulate the bone marrow in myeloproliferative neoplasms lack resolution. A hallmark of leukemic progression is the increase in pro-inflammatory cytokines, cellular inflammation, and an expansion of CD4 T cells. In this study, we demonstrate that this inflammatory milieu promotes pathogenic skewing of both regulatory and effector T cells. We characterized the altered CD4+ T cell compartment in chronic myeloid leukemia (CML) and we found that Tregs are unstable and dysregulated across leukemic tissues. Specifically, the CML environment effectively co-opts Treg function and stability. This contributes to a phenotype of immune activation as well as an increase of pathogenic inflammatory T cells. Notably, our findings reveal that Treg/Th17 ratios are disrupted in leukemia and that loss of Tregs and activation of Th17 cells influence disease progression. Additionally, we found that Treg-secreted IL-10 directly influences myeloid and neutrophil differentiation of leukemic progenitors has beneficial anti-inflammatory effects. We demonstrate that restoring Treg function and expanding their IL-10 production can be used therapeutically to limit leukemic progression. Our results support the hypothesis that Tregs are compromised during leukemic progression as a consequence of pro-inflammatory cytokines from the myeloid associated disease. These findings highlight how the Treg/Th17 balance regulates disease progression. Furthermore, these studies provide an avenue by which Treg secreted IL-10 can be used for therapeutic intervention in the context of hematopoietic malignancies.

Proinflammatory cytokine

10.4049/jimmunol.206.supp.22.02

Cite

Citations (0)

Dysregulated Activating and Inhibitory Receptors on Natural Killer Cells Predicts Immune Escape and Poor Outcomes in Acute Myeloid Leukemia

Blood (2022)

Amanda F O Costa Valeriya Kuznetsova L Marani Izabela Aparecida Lopes Larissa Sarri Binelli

10.1182/blood-2022-168178

Cite

Citations (1)

Imbalanced receptors, gene signatures, and function of NK subsets predicts poor clinical outcomes in AML

The Journal of Immunology (2023)

Amanda Costa Valeriya Kuznetsova Leticia O. Marani Izabela Aparecida Lopes Larissa Sarri Binelli

Abstract NK cells mediate anti-leukemic immunosurveillance in AML. We hypothesized that impaired NK cells predict poor outcomes in AML. We analyzed the expression of receptors on CD56 NK cell subsets and their corresponding ligands on the CD45dim blast by flow cytometry in 100 AML and 17 healthy bone marrows. Risk stratification, complete remission, relapse, measurable residual disease, overall survival, relapse-free survival, NK cell ligand expression, NK function, and degranulation were evaluated. Additionally, we mapped the transcriptional landscape of AML-NK cells using single-cell RNA-seq. The expression of activating receptors by CD56dim NK was decreased in adverse risk, relapse, and MRD+ patients. Inhibitory receptors were increased in adverse risk, relapse, and MRD+. NK cell activating ligands were decreased in patients with higher expression of the corresponding receptor while inhibitory ligands were increased. Patients with a lower frequency of CD56dim NK showed less degranulation and killing rates. Transcriptionally, we observed an enrichment of inflammatory-associated pathways and an upregulation of inhibitory receptors in AML, especially in patients with the worst prognosis. Our data indicate that NK exhaustion, with a high frequency of inhibitory receptors, leads to impaired cytotoxicity and can predict poor outcomes in AML. Also, a selective pressure in the expression of NK cell ligands on the AML blast together with imbalanced receptors may vary in both NK and leukemic cells. Closing these gaps in the knowledge of NK-mediated immune evasion in leukemia is of significant interest for targeting the leukemic microenvironment by NK cell-mediated immunotherapy. "division funds" - 3117175

10.4049/jimmunol.210.supp.72.09

Cite

Citations (0)

Inflammatory Cytokines Shape an Altered Immune Response During Myeloid Malignancies

Frontiers in Immunology (2021)

Virginia Camacho Valeriya Kuznetsova Robert S. Welner

The immune microenvironment is a critical driver and regulator of leukemic progression and hematological disease. Recent investigations have demonstrated that multiple immune components play a central role in regulating hematopoiesis, and dysfunction at the immune cell level significantly contributes to neoplastic disease. Immune cells are acutely sensitive to remodeling by leukemic inflammatory cytokine exposure. Importantly, immune cells are the principal cytokine producers in the hematopoietic system, representing an untapped frontier for clinical interventions. Due to a proinflammatory cytokine environment, dysregulation of immune cell states is a hallmark of hematological disease and neoplasia. Malignant immune adaptations have profound effects on leukemic blast proliferation, disease propagation, and drug-resistance. Conversely, targeting the immune landscape to restore hematopoietic function and limit leukemic expansion may have significant therapeutic value. Despite the fundamental role of the immune microenvironment during the initiation, progression, and treatment response of hematological disease, a detailed examination of how leukemic cytokines alter immune cells to permit, promote, or inhibit leukemia growth is lacking. Here we outline an immune-based model of leukemic transformation and highlight how the profound effect of immune alterations on the trajectory of malignancy. The focus of this review is to summarize current knowledge about the impacts of pro- and anti-inflammatory cytokines on immune cells subsets, their modes of action, and immunotherapeutic approaches with the potential to improve clinical outcomes for patients suffering from hematological myeloid malignancies.

Proinflammatory cytokine

10.3389/fimmu.2021.772408

Cite

Citations (24)

Perturbation of Invariant Natural Killer T cells by the Clonal Hematopoiesis-related inflammatory environment

The Journal of Immunology (2023)

Francesca Luca Valeriya Kuznetsova Alana Franceski Paran Goel Amanda Costa

Abstract Invariant Natural Killer T (iNKT) cells are T cells characterized by a semi-invariant TCR and NK markers. They respond to glycolipid antigens presented by the major histocompatibility complex (MHC)-like molecule CD1d. Our single-cell transcriptomic profiling of several tissues identified marrow iNKT as a unique subset, possibly modulating marrow homeostasis. However, little is known about their role in hematological malignancies and how the disease-related environment impacts iNKT cells. For example, clonal hematopoiesis of indeterminate potential (CHIP) corresponds to a condition in which mutated hematopoietic cells have an enhanced fitness and expansion, increasing the risk of leukemia and other diseases. Loss of TET2 in CHIP promotes myeloid skewing and inflammation. TET2 is a methycytosine dioxygenase catalyzing DNA demethylation of genes involved in proliferation, differentiation and oncogenesis. However, the impact that TET2 loss has on iNKT lineage output and function is yet to be defined. In our chimeric mouse model of CHIP, only 15% of TET2 mutants differentiate into iNKT. We also observe a decrease of non-transformed iNKT cells in the marrow of our mice, suggesting environmental inhibition. We expect these bystander iNKT cells to be functionally impaired where inflammation leads to their chromatin rewiring potentially contributing to disease. This is addressed by studying CHIP-exposed iNKT transcriptomes and chromatin accessibility. Understanding the molecular basis of the functional reprogramming by the disease-related inflammation will improve clinical outcomes for marrow transplantation and for the development of cellular therapies using iNKT cells.

CD1D

Reprogramming

10.4049/jimmunol.210.supp.237.01

Cite

Citations (0)

Optimization of flow plan of heating section of atmospheric-vacuum tubestill unit for gas condensate processing

Chemistry and Technology of Fuels and Oils (1988)

И. В. Егоров R. M. Usmanov S. G. Prokopyuk V. M. Karpus'Valeriya Kuznetsova

Section (typography)

10.1007/bf00725586

Cite

Citations (0)

Engineering Chimeric Antigen Receptors

Acta Naturae (2017)

Sergey V. Kulemzin Valeriya Kuznetsova Maksim Mamonkin Alexander V. Taranin Andrey A. Gorchakov

Chimeric antigen receptors (CARs) are recombinant protein molecules that redirect cytotoxic lymphocytes toward malignant and other target cells. The high feasibility of manufacturing CAR-modified lymphocytes for the therapy of cancer has spurred the development and optimization of new CAR T cells directed against a broad range of target antigens. In this review, we describe the main structural and functional elements constituting a CAR, discuss the roles of these elements in modulating the anti-tumor activity of CAR T cells, and highlight alternative approaches to CAR engineering.

10.32607/20758251-2017-9-1-6-14

Cite

Citations (20)

INFLAMMATORY CYTOKINES PERTURB NK CELL FUNCTION AND GENE SIGNATURE IN CHRONIC MYELOID LEUKEMIA

Hematology Transfusion and Cell Therapy (2022)

Valeriya Kuznetsova S Patel AFO Costa Francesca Luca A Franceski

Natural killer (NK) cells have the capacity to eliminate malignant cells by releasing cytotoxic granules, which makes them a potent anti-cancer immunotherapeutic. NK cells'mature phenotype and counts positively correlate with prolonged treatment-free survival in chronic myeloid leukemia (CML), while dysfunctional NK cells are predictive of relapse in CML patients. The molecular drivers of this impairment during leukemic progression remain unclear. Given the established role of inflammatory cytokines (namely IL1β, IL-6, GM-CSF, TNFα) in driving myeloid malignancies, we aimed to define their effect on NK cell phenotype and function using a unique pre-clinical chimeric mouse model of CML. We hypothesize that leukemic cytokines impede NK cell maturation and cytotoxicity and shift NK cells toward a pro-tumor cytokine-producing phenotype. We establish a chimeric mouse model of CML by transplanting bone marrow BCR-ABL+ CD45.2 cells into sub-lethally irradiated CD45.1 C57BL/6 wild-type mice. For controls, mice are transplanted with non-mutant cells. Such chimeras represent a robust model to study the exposure of non-transformed host cells to leukemia. At the endpoint, splenic, blood, and bone marrow NK cells are harvested and profiled by flow cytometry, RT-qPCR, scRNA-seq, or used for degranulation assay. Blood samples are collected to obtain serum. Consistent with clinical observations, NK cells are severely reduced in numbers and frequencies and display an immature phenotype and diminished expression of activating receptors (Nkp46, Ly49D) while upregulating inhibitory molecules (Lag-3, TIGIT, NKG2A) during leukemia. Moreover, CML-exposed NK cells have a higher proliferation rate and a greater cell death indicating perturbed homeostasis. We revealed a preferential loss of terminally mature CD27−CD11b+ NK subset in CML mice, suggesting a functional shift from cytotoxic phenotype toward the immature cytokine-producing. In agreement, CML-exposed NK cells show impaired cytotoxicity as measured by target-specific degranulation ex vivo. Next, we mapped the transcriptional landscape of CML-exposed NK cells using single-cell RNA-sequencing. We confirmed decreased gene expression of NK maturation and cytotoxicity markers (Itgam, Cx3cr1, Prf1, Gzma ) and upregulation of inhibitory molecules (Tigit, Lag-3, Pdcd1lg1/2) and proteins involved in the cell cycle and senescence (Mki67, Ccna, Ccnb ). Importantly, CML-exposed NK cells had significantly increased mRNA levels of inflammatory cytokines including IL1β, TNF, GM-CSF; cytokine receptors Il6st, Il-2Ra; and negative regulators of STAT signaling SOCS1/2/3 and CIS. Furthermore, IL-6-STAT3 and IL1β/TNF-signaling gene signatures were enriched in CML-exposed NK cells – an effect that is likely to be triggered by inflammatory cytokines. Thus, we next found that peripheral blood serum from CML mice dampens healthy NK cell degranulation ex vivo, compared to serum from control mice. Further ELISA analysis revealed elevated levels of IL-6, IL-1, TNF, and GM-CSF in CML serum samples. Some of these cytokines might be secreted by functionally skewed NK cells, as suggested by gene expression analysis. Altogether, our data suggest that leukemic cytokines contribute to NK cell dysfunction and polarize them toward a pro-inflammatory phenotype, representing optimal targets for NK-boosting CML immunotherapies.

TIGIT

10.1016/j.htct.2022.09.365

Cite

Citations (0)

Modular lentiviral vector system for chimeric antigen receptor design optimization

Russian Journal of Bioorganic Chemistry (2017)

Sergey V. Kulemzin N. A. Chikaev Olga Y. Volkova Valeriya Kuznetsova Alexander V. Taranin

Linker

Cancer Immunotherapy

10.1134/s1068162017020091

Cite

Citations (6)