Publications by authors named "Thomas E Bickett"

8 Publications

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FLT3L release by NK cells enhances response to radioimmunotherapy in preclinical models of HNSCC.

Clin Cancer Res 2021 Sep 13. Epub 2021 Sep 13.

Radiation Oncology, University of Colorado Denver

Purpose: Natural Killer (NK) cells are type 1 innate lymphoid cells that are known to secrete cytokines and for their role in killing virally infected cells or cancer cells through cytotoxicity. In addition to direct tumor cell killing, NK cells are known to play fundamental roles in the tumor microenvironment through secretion of key cytokines such as FMS-like tyrosine kinase 3 ligand (FLT3L). Although radiation therapy (RT) is the mainstay treatment most cancers, the role of radiation therapy on NK cells is not well characterized.

Experimental Design: This study combines radiation, immunotherapies, genetic mouse models, and antibody depletion experiments to identify the role of NK cells in overcoming resistance to RT in orthotopic models of head and neck squamous cell carcinoma.

Results: We have found that NK cells are a crucial component in the development of an anti-tumor response, as depleting them removes efficacy of the previously successful combination treatment of RT, anti-CD25 and anti-CD137. However, in the absence of NK cells, the effect can be rescued through treatment with FLT3L. But neither RT with FLT3L therapy alone nor RT with anti-NKG2A yields any meaningful tumor growth delay. We also identify a role for IL-2 in activating NK cells to secrete FLT3L. This activity is mediated through CD122, the intermediate affinity IL-2 receptor and can be targeted with anti-CD25.

Conclusions: These findings highlight the complexity of using radio-immunotherapies to activate NK cells within the tumor microenvironment, and the importance of NK cells in activating dendritic cells for increased tumor surveillance.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0971DOI Listing
September 2021

Targeting resistance to radiation-immunotherapy in cold HNSCCs by modulating the Treg-dendritic cell axis.

J Immunother Cancer 2021 Apr;9(4)

Department of Radiation Oncology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA

Background: Numerous trials combining radiation therapy (RT) and immunotherapy in head and neck squamous cell carcinoma (HNSCC) are failing. Using preclinical immune cold models of HNSCC resistant to RT-immune checkpoint inhibitors, we investigate therapeutic approaches of overcoming such resistance by examining the differential microenvironmental response to RT.

Methods: We subjected two HPV-negative orthotopic mouse models of HNSCC to combination RT, regulatory T cells (Treg) depletion, and/or CD137 agonism. Tumor growth was measured and intratumorous and lymph node immune populations were compared among treatment groups. Human gene sets, genetically engineered mouse models and , flow and time-of-flight cytometry, RNA-Seq, Treg adoptive transfer studies, and in vitro experiments were used to further evaluate the role of dendritic cells (DCs) and Tregs in these treatments.

Results: In MOC2 orthotopic tumors, we find no therapeutic benefit to targeting classically defined immunosuppressive myeloids, which increase with RT. In these radioresistant tumors, supplementing combination RT and Treg depletion with anti-CD137 agonism stimulates CD103 DC activation in tumor-draining lymph nodes as characterized by increases in CD80 and CCR7 DCs, resulting in a CD8 T cell-dependent response. Simultaneously, Tregs are reprogrammed to an effector phenotype demonstrated by increases in interferonγ, tumor necrosis factorα, PI3K, pAKT and Eomes populations as well as decreases in CTLA4 and NRP-1 populations. Tumor eradication is observed when RT is increased to an 8 Gy x 5 hypofractionated regimen and combined with anti-CD25+ anti-CD137 treatment. In a human gene set from oral squamous cell carcinoma tumors, high Treg number is associated with earlier recurrence.

Conclusions: Regulating Treg functionality and DC activation status within the lymph node is critical for generating a T cell effector response in these highly radioresistant tumors. These findings underscore the plasticity of Tregs and represent a new therapeutic opportunity for reprogramming the tumor microenvironment in HNSCCs resistant to conventional radioimmunotherapy approaches.
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http://dx.doi.org/10.1136/jitc-2020-001955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061827PMC
April 2021

Complement C3a and C5a receptor blockade modulates regulatory T cell conversion in head and neck cancer.

J Immunother Cancer 2021 03;9(3)

Radiation Oncology, University of Colorado-Anschutz Medical Campus, Aurora, Colorado, USA

Background: Resistance to therapy is a major problem in treating head and neck squamous cell carcinomas (HNSCC). Complement system inhibition has been shown to reduce tumor growth, metastasis, and therapeutic resistance in other tumor models, but has yet to be explored in the context of HNSCC. Here, we tested the effects of complement inhibition and its therapeutic potential in HNSCC.

Methods: We conducted our studies using two Human Papilloma Virus (HPV)-negative HNSCC orthotopic mouse models. Complement C3aR and C5aR1 receptor antagonists were paired with radiation therapy (RT). Tumor growth was measured and immune populations from tumor, lymph node, and peripheral blood were compared among various treatment groups. Genetically engineered mouse models were used in addition to standard wild type models. Flow cytometry, clinical gene sets, and in vitro assays were used to evaluate the role complement receptor blockade has on the immunological makeup of the tumor microenvironment.

Results: In contrast to established literature, inhibition of complement C3a and C5a signaling using receptor antagonists accelerated tumor growth in multiple HNSCC cell lines and corresponded with increased frequency of regulatory T cell (Treg) populations. Local C3a and C5a signaling has importance for CD4 T cell homeostasis and eventual development into effector phenotypes. Interruption of this signaling axis drives a phenotypic conversion of CD4 T cells into Tregs, characterized by enhanced expression of Foxp3. Depletion of Tregs reversed tumor growth, and combination of Treg depletion and C3a and C5a receptor inhibition decreased tumor growth below that of the control groups. Complete knockout of C3 does not harbor the expected effect on tumor growth, indicating a still undetermined compensatory mechanism. Dexamethasone is frequently prescribed to patients undergoing RT and inhibits complement activation. We report no deleterious effects associated with dexamethasone due to complement inhibition.

Conclusions: Our data establish Tregs as a pro-tumorigenic driver during complement inhibition and provide evidence that targeted C3a and C5a receptor inhibition may add therapeutic advantage when coupled with anti-Treg therapy.
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http://dx.doi.org/10.1136/jitc-2021-002585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016081PMC
March 2021

Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer.

Cancer Res 2021 Jun 1;81(12):3255-3269. Epub 2021 Feb 1.

Department of Pharmacology, University of Colorado Comprehensive Cancer Center, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.

Stromal fibrosis activates prosurvival and proepithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell-surface proteins, a disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after radiation therapy (RT). RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with ephrinB2 FC protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after RT and identifies a targetable pathway to enhance RT efficacy. SIGNIFICANCE: Targeting a previously unidentified adaptive resistance mechanism to radiation therapy in PDAC tumors in combination with radiation therapy could increase survival of the 40% of PDAC patients with locally advanced disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3255/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260469PMC
June 2021

Tuberculosis-Cancer Parallels in Immune Response Regulation.

Int J Mol Sci 2020 Aug 26;21(17). Epub 2020 Aug 26.

Department of Radiation/Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80022, USA.

and cancer are two diseases with proclivity for the development of resistance to the host immune system. Mechanisms behind resistance can be host derived or disease mediated, but they usually depend on the balance of pro-inflammatory to anti-inflammatory immune signals. Immunotherapies have been the focus of efforts to shift that balance and drive the response required for diseases eradication. The immune response to tuberculosis has widely been thought to be T cell dependent, with the majority of research focused on T cell responses. However, the past decade has seen greater recognition of the importance of the innate immune response, highlighting factors such as trained innate immunity and macrophage polarization to mycobacterial clearance. At the same time, there has been a renaissance of immunotherapy treatments for cancer since the first checkpoint inhibitor passed clinical trials, in addition to work highlighting the importance of innate immune responses to cancer. However, there is still much to learn about host-derived responses and the development of resistance to new cancer therapies. This review examines the similarities between the immune responses to cancer and tuberculosis with the hope that their commonalities will facilitate research collaboration and discovery.
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http://dx.doi.org/10.3390/ijms21176136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503600PMC
August 2020

Characterizing the BCG Induced Macrophage and Neutrophil Mechanisms for Defense Against .

Front Immunol 2020 18;11:1202. Epub 2020 Jun 18.

Department of Microbiology Immunology and Pathology, Cell and Molecular Biology, Colorado State University, Fort Collins, CO, United States.

The live attenuated strain, Bacille Calmette Guérin (BCG) is a potent innate immune stimulator. In the C57BL/6 mouse model of tuberculosis, BCG vaccination leads to a significant reduction of burden after aerogenic infection. Our studies indicated that BCG induced protection against pulmonary tuberculosis was independent of T cells and present as early as 7 days after vaccination. This protection showed longevity, as it did not wane when conventional T cell and TNF-α deficient mice were infected 30 days post-vaccination. As BCG induced mycobacterial killing after 7 days, this study investigated the contributions of the innate immune system after BCG vaccination to better understand mechanisms required for mycobacterial killing. Subcutaneous BCG inoculation resulted in significant CD11bF4/80 monocyte subset recruitment into the lungs within 7 days. Further studies revealed that killing of mycobacteria was dependent on the viability of BCG, because irradiated BCG did not have the same effect. Although others have identified BCG as a facilitator of trained innate immunity, we found that BCG reduced the mycobacterial burden in the absence of mechanisms required for trained innate immunity, highlighting a role for macrophages and neutrophils for vaccine induced killing of .
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http://dx.doi.org/10.3389/fimmu.2020.01202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314953PMC
April 2021

Contributions of Influenza Virus Hemagglutinin and Host Immune Responses Toward the Severity of Influenza Virus: Streptococcus pyogenes Superinfections.

Viral Immunol 2018 Jul/Aug;31(6):457-469. Epub 2018 Jun 5.

1 Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota , Vermillion, South Dakota.

Influenza virus infections can be complicated by bacterial superinfections, which are medically relevant because of a complex interaction between the host, the virus, and the bacteria. Studies to date have implicated several influenza virus genes, varied host immune responses, and bacterial virulence factors, however, the host-pathogen interactions that predict survival versus lethal outcomes remain undefined. Previous work by our group showed that certain influenza viruses could yield a survival phenotype (A/swine/Texas/4199-2/98-H3N2, TX98), whereas others were associated with a lethal phenotype (A/Puerto Rico/8/34-H1N1, PR8). Based on this observation, we developed the hypothesis that individual influenza virus genes could contribute to a superinfection, and that the host response after influenza virus infection could influence superinfection severity. The present study analyzes individual influenza virus gene contributions to superinfection severity using reassortant viruses created using TX98 and PR8 viral genes. Host and pathogen interactions, relevant to survival and lethal phenotypes, were studied with a focus on pathogen clearance, host cellular infiltrates, and cytokine levels after infection. Specifically, we found that the hemagglutinin gene expressed by an influenza virus can contribute to the severity of a secondary bacterial infection, likely through modulation of host proinflammatory responses. Altogether, these results advance our understanding of molecular mechanisms underlying influenza virus-bacteria superinfections and identify viral and corresponding host factors that may contribute to morbidity and mortality.
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http://dx.doi.org/10.1089/vim.2017.0193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043403PMC
October 2018

Vaccination against the M protein of Streptococcus pyogenes prevents death after influenza virus: S. pyogenes super-infection.

Vaccine 2014 Sep 29;32(40):5241-9. Epub 2014 Jul 29.

Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, United States. Electronic address:

Influenza virus infections are associated with a significant number of illnesses and deaths on an annual basis. Many of the deaths are due to complications from secondary bacterial invaders, including Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pyogenes. The β-hemolytic bacteria S. pyogenes colonizes both skin and respiratory surfaces, and frequently presents clinically as strep throat or impetigo. However, when these bacteria gain access to normally sterile sites, they can cause deadly diseases including sepsis, necrotizing fasciitis, and pneumonia. We previously developed a model of influenza virus:S. pyogenes super-infection, which we used to demonstrate that vaccination against influenza virus can limit deaths associated with a secondary bacterial infection, but this protection was not complete. In the current study, we evaluated the efficacy of a vaccine that targets the M protein of S. pyogenes to determine whether immunity toward the bacteria alone would allow the host to survive an influenza virus:S. pyogenes super-infection. Our data demonstrate that vaccination against the M protein induces IgG antibodies, in particular those of the IgG1 and IgG2a isotypes, and that these antibodies can interact with macrophages. Ultimately, this vaccine-induced immunity eliminated death within our influenza virus:S. pyogenes super-infection model, despite the fact that all M protein-vaccinated mice showed signs of illness following influenza virus inoculation. These findings identify immunity against bacteria as an important component of protection against influenza virus:bacteria super-infection.
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http://dx.doi.org/10.1016/j.vaccine.2014.06.093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146501PMC
September 2014
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