Dr. Suresh Kalathil, Ph.D - Roswell Park Cancer Institute - HRI Scientist

Dr. Suresh Kalathil

Ph.D

Roswell Park Cancer Institute

HRI Scientist

Buffalo, NY | United States

Additional Specialties: Tumor immunology

ORCID logohttps://orcid.org/0000-0002-7800-3151

Dr. Suresh Kalathil, Ph.D - Roswell Park Cancer Institute - HRI Scientist

Dr. Suresh Kalathil

Ph.D

Introduction

Primary Affiliation: Roswell Park Cancer Institute - Buffalo, NY , United States

Additional Specialties:

Research Interests:

Education

Sep 2009
Roswell Park Cancer Institute
Ph.D
Immunology

Experience

Aug 2009
Roswell Park Cancer Institute
HRI Scientist
Immunology

Publications

18Publications

544Reads

98Profile Views

658PubMed Central Citations

An Animal Model of Inhaled Vitamin E Acetate and EVALI-like Lung Injury.

N Engl J Med 2020 03 26;382(12):1175-1177. Epub 2020 Feb 26.

Roswell Park Comprehensive Cancer Center, Buffalo, NY

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http://dx.doi.org/10.1056/NEJMc2000231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299285PMC
March 2020
55.873 Impact Factor

An Animal Model of Inhaled Vitamin E Acetate and EVALI-like Lung Injury

17

New England Journal of Medicine

https://www.nejm.org/doi/full/10.1056/NEJMc2000231?query=TOCAn Animal Model of Inhaled Vitamin E Acetate and EVALI-like Lung Injury February 26, 2020 DOI: 10.1056/NEJMc2000231 Metrics To the Editor: As of February 4, 2020, electronic-cigarette, or vaping, product use–associated lung injury (EVALI) has resulted in the hospitalization of 2758 people across the United States and has been linked to at least 64 deaths (www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html. opens in new tab). Although recent testing by the Centers for Disease Control and Prevention showed the presence of vitamin E acetate in bronchoalveolar-lavage (BAL) fluid samples obtained from patients with EVALI,1,2 additional studies are necessary to determine whether a causal link exists between inhalation of vitamin E acetate and EVALI.Figure 1. Figure 1. Findings from a Mouse Model of Electronic-Cigarette, or Vaping, Product Use–Associated Lung Injury (EVALI). Panel A shows levels of vitamin E acetate (VEA) quantified by isotope-dilution mass spectrometry in bronchoalveolar-lavage (BAL) fluid harvested from mice. Values are means and standard deviations for 10 mice. Panel B shows albumin levels measured in BAL fluid from mice exposed to air, a mixture of propylene glycol and vegetable glycerin (PG–VG), or VEA. Values are means and standard deviations for 10 mice. Panel C shows the total number of CD45+ cells infiltrating the lung in mice exposed to air, PG–VG, or VEA. Values are means and standard deviations for 10 mice. The P values in Panels A, B, and C were calculated by two-way analysis of variance in Tukey’s post-test comparisons among the exposure groups. Panel D shows BAL fluid from a mouse exposed to VEA, containing lipid-laden macrophages (representative examples are indicated with arrows) with cytoplasmic staining by oil red O in a vesicular pattern. The macrophages are numerous and contain variable amounts of lipid. Background pneumocytes (arrowheads) show comparatively scant cytoplasm and are present as single cells or loose sheets. Panel E shows BAL fluid from a mouse exposed to PG–VG, which contained fewer identifiable macrophages and had minimal to no specific staining by oil red O. Without lipid staining, it is more difficult to distinguish between small alveolar macrophages and pneumocytes in these preparations. Panels F and G show findings in lung sections. In mice exposed to VEA (Panel F), alveolar macrophages (arrowheads and circles) in residence among pneumocytes (P) lining the alveoli (A) contained abundant oil red O–stained lipid. In mice exposed to PG–VG, tiny oil red O–stained granules in the cytoplasm of cells lining the alveoli, including pneumocytes (arrows) and alveolar macrophages (arrowheads), were observed. B denotes bronchiole.We exposed 30 mice (in three groups of 10) to aerosols generated from vitamin E acetate, a mixture of propylene glycol and vegetable glycerin (PG–VG), or air (controls). We estimated that the mice exposed to vitamin E acetate in our experiments would have inhaled 77.3 to 167.5 μg of vitamin E acetate per gram of body weight per day, a dose equivalent to the amount that an adult e-cigarette user would inhale by daily use of 0.52 to 1.13 ml of vaping product containing 88% vitamin E acetate. The levels of vitamin E acetate measured in mouse BAL fluid (Figure 1A) suggest that this chemical was effectively delivered to the lungs of the exposed mice and match the findings of vitamin E acetate in BAL fluid from patients with EVALI.1,2 At the end of the 2-week exposure period, the mice were euthanized, BAL fluid was harvested, and lung sections were examined by a pathologist. The details of study procedures are provided in the Supplementary Appendix. opens in new tab, available with the full text of this letter at NEJM.org.Numerous markers measured in our study indicated that pulmonary injury was present after inhalation of vitamin E acetate aerosols. Exposure to vitamin E acetate increased the levels of albumin in BAL fluid (a surrogate marker of lung epithelial damage) to a greater extent than exposure to PG–VG or to air (Figure 1B). The total numbers of leukocytes in the lungs of mice exposed to vitamin E acetate were significantly higher than those in mice exposed to PG–VG or to air (Figure 1C). Cells isolated from the BAL fluid of vitamin E acetate–exposed mice contained numerous lipid-laden macrophages (Figure 1D), a finding consistent with clinical observations in patients with EVALI.3,4 BAL cells recovered from mice exposed to PG–VG contained fewer identifiable macrophages, and there was no specific staining by oil red O (Figure 1E). Examination of lung-tissue sections from mice exposed to vitamin E acetate revealed alveolar macrophages containing abundant oil red O–stained lipid, often in clusters, residing with pneumocytes lining the alveoli (Figure 1F). In contrast, tiny oil red O–stained granules in the cytoplasm of cells lining the alveoli were observed in mice exposed to PG–VG (Figure 1G).This study contributes to our understanding of EVALI through the development of an animal model that can be used to evaluate the potential role of the suspected toxicant vitamin E acetate. A limitation of the study is that the aerosols generated by an e-cigarette may contain by-products of the thermal degradation of vitamin E acetate after heating. A chemical evaluation of the generated aerosols would be required to identify such by-products. Another limitation is that we did not expose animals to aerosols that contained tetrahydrocannabinol (THC) or nicotine in a dose-dependent manner. Finally, it is possible that aerosols generated from other lipophilic solvents may produce outcomes similar to the outcome seen with vitamin E acetate in this study. Future studies are needed to address these issues. Our findings, coupled with previous research identifying vitamin E acetate in BAL fluid from patients with EVALI1,2 and in samples of case-associated product liquids,5 provide additional evidence for vitamin E acetate as a possible cause of EVALI.Tariq A. Bhat, Ph.D.Suresh G. Kalathil, Ph.D.Paul N. Bogner, M.D.Roswell Park Comprehensive Cancer Center, Buffalo, NYBenjamin C. Blount, Ph.D.Centers for Disease Control and Prevention, Atlanta, GAMaciej L. Goniewicz, Ph.D., Pharm.D.Yasmin M. Thanavala, Ph.D.Roswell Park Comprehensive Cancer Center, Buffalo, NY yasmin.thanavala@roswellpark.orgSupported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01HL142511), the National Cancer Institute (NCI) (P30CA016056), and the NCI and the Center for Tobacco Products of the Food and Drug Administration (U54CA228110).Disclosure forms. opens in new tab provided by the authors are available with the full text of this letter at NEJM.org.The views and opinions expressed in this letter are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, the National Institutes of Health, or the Food and Drug Administration.This letter was published on February 26, 2020, at NEJM.org.Dr. Blount is a member of the Lung Injury Response Lab Task Force; additional members are listed in the Supplementary Appendix. opens in new tab, available with the full text of this letter at NEJM.org.5 References1. Blount BC, Karwowski MP, Morel-Espinosa M, et al. Evaluation of bronchoalveolar lavage fluid from patients in an outbreak of e-cigarette, or vaping, product use–associated lung injury — 10 states, August–October 2019. MMWR Morb Mortal Wkly Rep 2019;68:1040-1041.Crossref. opens in new tabWeb of Science. opens in new tabMedline. opens in new tabGoogle Scholar. opens in new tab2. Blount BC, Karwowski MP, Shields PG, et al. Vitamin E acetate in bronchoalveolar-lavage fluid associated with EVALI. N Engl J Med 2020;382:697-705.Free Full TextMedline. opens in new tabGoogle Scholar. opens in new tab3. Layden JE, Ghinai I, Pray I, et al. Pulmonary illness related to e-cigarette use in Illinois and Wisconsin — preliminary report. N Engl J Med. DOI: .Free Full TextMedline. opens in new tabGoogle Scholar. opens in new tab4. Maddock SD, Cirulis MM, Callahan SJ, et al. Pulmonary lipid-laden macrophages and vaping. N Engl J Med 2019;381:1488-1489.Free Full TextWeb of Science. opens in new tabMedline. opens in new tabGoogle Scholar. opens in new tab5. Krishnasamy VP, Hallowell BD, Ko JY, et al. Update: characteristics of a nationwide outbreak of e-cigarette, or vaping, product use–associated lung injury — United States, August 2019–January 2020. MMWR Morb Mortal Wkly Rep 2020;69:90-94.Crossref. opens in new tabMedline. opens in new tabGoogle Scholar. opens in new tab Supplementary Material Supplementary Appendix. opens in new tabPDF136KBDisclosure Forms. opens in new tabPDF199KB . opens in new tab Share FacebookFacebookTwitterTwitterLinkedInLinkedIn. opens in new tab Email Copy URL More Download Citation Permissions Article Alert Reprints More aboutPulmonary/​Critical CareCritical CareDrugs, Devices, and the FDAPublic Health

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February 2020

Impact Factor 72.000

3 Reads

Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy.

JCI Insight 2019 08 8;4(15). Epub 2019 Aug 8.

Department of Immunology.

BACKGROUNDSorafenib has been shown to reduce the extent of immunosuppression in patients with hepatocellular carcinoma (HCC). The rationale of this investigation was to identify biomarkers that can predict treatment efficacy of sorafenib in HCC patients and to unravel the mechanism by which sorafenib impedes immune suppression mediated by distinct immunosuppressive cell subsets.METHODSWith informed consent, blood samples were collected from 30 patients with advanced HCC, at baseline and 2 time points after initiation of sorafenib treatment. The frequency of PD-1+ T cells, ERK2 phosphorylation on flt-3+ Tregs and MDSCs, and T effector cell function were quantified by using flow cytometry.RESULTSElevated levels of CD8+Ki67+ T cells producing IFN-? were associated with improved progression-free survival and overall survival (OS). High frequencies of these T cells were correlated with significantly reduced risk of death over time. Patients with an increased pretreatment T effector/Treg ratio showed significant improvement in OS. ERK+flt-3+ Tregs and MDSCs were significantly decreased after sorafenib therapy. Increased numbers of baseline flt-3+p-ERK+ MDSCs were associated with survival benefit of patients.CONCLUSIONA high baseline CD4+ T effector/Treg ratio is a potential biomarker of prognostic significance in HCC. CD8+Ki67+ T cells producing IFN-? are a key biomarker of response to sorafenib therapy resulting in survival benefit. The immune modulation resulted from sorafenib-mediated blockade of signaling through the VEGF/VEGFR/flt-3 pathway, affecting ERK phosphorylation. These insights may help identify patients who likely would benefit from VEGFR antagonism and inform efforts to improve the efficacy of sorafenib in combination with immunotherapy.TRIAL REGISTRATIONNCT02072486.FUNDINGNational Comprehensive Cancer Network Oncology Research Program from general research support provided by Bayer US LLC (NCCNSORA0002), National Cancer Institute grant P30CA016056, and pilot funds from Roswell Park Alliance Foundation.

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http://dx.doi.org/10.1172/jci.insight.130116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693832PMC
August 2019
9 Reads
9 Citations
6.040 Impact Factor

PD-1+ and Foxp3+ T cell reduction correlates with survival of HCC patients after sorafenib therapy

10.1172/jci.insight.86182

JCI insight

BACKGROUND. Sorafenib is an oral antiangiogenic agent administered in advanced-stage hepatocellular carcinoma (HCC). Based on preclinical and human studies, we hypothesized that, in addition to its antiangiogenic properties, sorafenib may beneficially reduce the extent of the immunosuppressive network in HCC patients. To test this hypothesis, we examined whether alterations in the immunosuppressive burden of advanced-stage HCC patients correlated with clinical outcome.

METHODS. In before and after sorafenib treatment, blood samples collected from 19 patients with advanced HCC, the frequency of PD-1+ T cells, Tregs, and myeloid derived suppressor cells (MDSC) were quantified by multiparameter FACS. Cytokine levels in plasma were determined by ELISA.

RESULTS. Overall survival (OS) was significantly impacted by the reduction in the absolute number of both CD4+PD-1+ T cells and CD8+PD-1+ T cells following sorafenib treatment. Significant decreases in the frequency and absolute number of Foxp3+ Tregs were also observed, and a statistically significant improvement in OS was noted in patients exhibiting a greater decrease in the number of Foxp3+ Tregs. The ratio of CD4+CD127+PD-1 T effector cells to CD4+Foxp3+PD-1+ Tregs was significantly increased following treatment with sorafenib. Increased frequency of CD4+CD127+ T effector cells in the posttreatment samples significantly correlated with OS.

CONCLUSION. This study is the first to our knowledge to demonstrate the potent immunomodulatory effects of sorafenib therapy on PD-1+ T cells and Tregs and the ensuing correlation with survival. These phenotypes could serve as predictive biomarkers to identify HCC patients who are likely to benefit from sorafenib treatment.

TRIAL REGISTRATION. Registration is not required for observational studies.

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July 2019

31 Citations

Impact Factor 6.040

13 Reads

Secondhand Smoke Induces Inflammation and Impairs Immunity to Respiratory Infections.

J Immunol 2018 04 19;200(8):2927-2940. Epub 2018 Mar 19.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263;

Despite advocacy to reduce smoking-related diseases, >1 billion people worldwide continue to smoke. Smoking is immunosuppressive and an important etiological factor in the development of several human disorders including respiratory diseases like chronic obstructive pulmonary disease. However, there is a critical gap in the knowledge of the role of secondhand smoke (SHS) in inflammation and immunity. We therefore studied the influence of SHS on pulmonary inflammation and immune responses to respiratory infection by nontypeable (NTHI) recurrently found in chronic obstructive pulmonary disease patients. Chronic SHS-exposed mice were chronically infected with NTHI and pulmonary inflammation was evaluated by histology. Immune cell numbers and cytokines were measured by flow cytometry and ELISA, respectively. Chronic SHS exposure impaired NTHI P6 Ag-specific B and T cell responses following chronic NTHI infection as measured by ELISPOT assays, reduced the production of Abs in serum and bronchoalveolar lavage, and enhanced albumin leak into the bronchoalveolar lavage as determined by ELISA. Histopathological examination of lungs revealed lymphocytic accumulation surrounding airways and bronchovasculature following chronic SHS exposure and chronic infection. Chronic SHS exposure enhanced the levels of inflammatory cytokines IL-17A, IL-6, IL-1?, and TNF-? in the lungs, and impaired the generation of adaptive immunity following either chronic infection or P6 vaccination. Chronic SHS exposure diminished bacterial clearance from the lungs after acute NTHI challenge, whereas P6 vaccination improved clearance equivalent to the level seen in air-exposed, non-vaccinated mice. Our study provides unequivocal evidence that SHS exposure has long-term detrimental effects on the pulmonary inflammatory microenvironment and immunity to infection and vaccination.

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http://dx.doi.org/10.4049/jimmunol.1701417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922268PMC
April 2018
9 Reads
11 Citations
4.922 Impact Factor

Endothelial progenitor cell number and ERK phosphorylation serve as predictive and prognostic biomarkers in advanced hepatocellular carcinoma patients treated with sorafenib.

Oncoimmunology 2016 20;5(10):e1226718. Epub 2016 Sep 20.

Department of Immunology, Roswell Park Cancer Institute , Buffalo, NY, USA.

Sorafenib is an oral anti-angiogenic multi-kinase inhibitor used for systemic therapy in patients with advanced hepatocellular carcinoma (HCC) who are not suitable candidates for surgery or liver transplantation. An earlier study conducted with HCC tumor tissue suggested that ERK phosphorylation (pERK), a downstream target of sorafenib, may serve as a potential biomarker for therapeutic efficacy of sorafenib. However, no study thus far has utilized a minimal invasive procedure to predict HCC patient responsiveness to sorafenib. We evaluated the biomarker utility of circulating endothelial progenitor cells (EPCs) frequency and intracellular pERK levels in EPCs in peripheral blood obtained pre- and post-sorafenib therapy or after transarterial chemoembolistaion (TACE). A statistically significant reduction in the level of ERK phosphorylation and in the absolute number of EPCs was detected following sorafenib treatment ( < 0 .01 for both). In contrast, the decrease in the level of ERK phosphorylation and EPC number was either marginally significant or insignificant in patients treated with TACE ( = 0.05 and 0.06, respectively). sorafenib treatment of pre- and post-samples from the same patient cohort inhibited ERK phosphorylation levels in EPCs and decreased the number of EPCs at all doses tested ( = 0.01). Our findings support that the evaluation of both the circulating EPC frequency and the level of ERK phosphorylation in EPCs may serve as potential non-invasive biomarkers of sorafenib efficacy, both as predictor of treatment outcome and efficacy during drug treatment.

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http://dx.doi.org/10.1080/2162402X.2016.1226718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087301PMC
September 2016
16 Reads
9 Citations
7.700 Impact Factor

High immunosuppressive burden in cancer patients: a major hurdle for cancer immunotherapy.

Cancer Immunol Immunother 2016 07 24;65(7):813-9. Epub 2016 Feb 24.

Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.

A bottleneck for immunotherapy of cancer is the immunosuppressive microenvironment in which the tumor cells are located. Regardless of the fact that large numbers of tumor-specific T cells can be generated in patients by active immunization or adoptive transfer, these T cells do not readily translate to tumor cell killing in vivo. The immune regulatory mechanism that prevents autoimmunity may be harnessed by tumor cells for the evasion of immune destruction. Regulatory T cells, myeloid-derived suppressor cells, inhibitory cytokines and immune checkpoint receptors are the major components of the immune system acting in concert with causing the subversion of anti-tumor immunity in the tumor microenvironment. This redundant immunosuppressive network may pose an impediment to efficacious immunotherapy, thus facilitating tumor progression. Cancer progression clearly documents the failure of immune control over relentless growth of tumor cells. Detailed knowledge of each of these factors responsible for creating an immunosuppressive shield to protect tumor cells from immune destruction is essential for the development of novel immune-based therapeutic interventions of cancer. Multipronged targeted depletion of these suppressor cells may restore production of granzyme B by CD8(+) T cells and increase the number of IFN-?-producing CD4(+) T cells.

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http://dx.doi.org/10.1007/s00262-016-1810-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714319PMC
July 2016
3 Reads
24 Citations
4.500 Impact Factor

PD-1 and Foxp3 T cell reduction correlates with survival of HCC patients after sorafenib therapy.

JCI Insight 2016 Jul;1(11)

Department of Immunology, Roswell Park Cancer Institute (RPCI), Buffalo, New York, USA.

Background: Sorafenib is an oral antiangiogenic agent administered in advanced-stage hepatocellular carcinoma (HCC). Based on preclinical and human studies, we hypothesized that, in addition to its antiangiogenic properties, sorafenib may beneficially reduce the extent of the immunosuppressive network in HCC patients. To test this hypothesis, we examined whether alterations in the immunosuppressive burden of advanced-stage HCC patients correlated with clinical outcome.

Methods: In before and after sorafenib treatment, blood samples collected from 19 patients with advanced HCC, the frequency of PD-1 T cells, Tregs, and myeloid derived suppressor cells (MDSC) were quantified by multiparameter FACS. Cytokine levels in plasma were determined by ELISA.

Results: Overall survival (OS) was significantly impacted by the reduction in the absolute number of both CD4PD-1 T cells and CD8PD-1 T cells following sorafenib treatment. Significant decreases in the frequency and absolute number of Foxp3 Tregs were also observed, and a statistically significant improvement in OS was noted in patients exhibiting a greater decrease in the number of Foxp3 Tregs. The ratio of CD4CD127PD-1 T effector cells to CD4Foxp3PD-1 Tregs was significantly increased following treatment with sorafenib. Increased frequency of CD4CD127 T effector cells in the posttreatment samples significantly correlated with OS.

Conclusion: This study is the first to our knowledge to demonstrate the potent immunomodulatory effects of sorafenib therapy on PD-1 T cells and Tregs and the ensuing correlation with survival. These phenotypes could serve as predictive biomarkers to identify HCC patients who are likely to benefit from sorafenib treatment.

Trial Registration: Registration is not required for observational studies.

Funding: This study was supported by NCI Core Grant to RPCI (NIH P30 CA016056) and discretionary funds to Y. Thanavala.

http://www.targetedonc.com/publications/hcc-monitor/2016/september-2016/new-evidence-supports-a-key-role-of-the-immune-system-in-hcc?p=2

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http://dx.doi.org/10.1172/jci.insight.86182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986927PMC
July 2016
242 Reads
29 Citations

Immune Dysfunction in Patients with Chronic Obstructive Pulmonary Disease.

Ann Am Thorac Soc 2015 Nov;12 Suppl 2:S169-75

Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.

Chronic obstructive pulmonary disease (COPD) is a complex chronic disease. Chronic inflammation is the hallmark of COPD, involving the interplay of a wide variety of cells in the lung microenvironment. Cigarette smoke (CS) induces chronic lung inflammation and is considered a key etiological factor in the development and pathogenesis of COPD. Structural and inflammatory cells in the lung respond to CS exposure by releasing proinflammatory mediators that recruit additional inflammatory immune cells, which collectively contribute to the establishment of a chronic inflammatory microenvironment. Chronic inflammation contributes to lung damage, compromises innate and adaptive immune responses, and facilitates the recurrent episodes of respiratory infection that punctuate and further contribute to the pathological manifestations of the stable disease. A number of studies support the conclusion that immune dysfunction leads to exacerbations and disease severity in COPD. Our group has clearly demonstrated that CS exacerbates lung inflammation and compromises immunity to respiratory pathogens in a mouse model of COPD. We have also investigated the phenotype of immune cells in patients with COPD compared with healthy control subjects and found extensive immune dysfunction due to the presence and functional activity of T regulatory cells, CD4(+)PD-1(+) exhausted effector T cells and myeloid-derived suppressor cells. Manipulation of these immunosuppressive networks in COPD could provide a rational strategy to restore functional immune responses, reduce exacerbations, and improve lung function. In this review, we discuss the role of immune dysfunction in COPD that may contribute to recurrent respiratory infections and disease severity.

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http://dx.doi.org/10.1513/AnnalsATS.201503-126AWDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722840PMC
November 2015
4 Reads
62 Citations

T-regulatory cells and programmed death 1+ T cells contribute to effector T-cell dysfunction in patients with chronic obstructive pulmonary disease.

Am J Respir Crit Care Med 2014 Jul;190(1):40-50

1 Department of Immunology and.

Rationale: Previous studies from our laboratory have shown that peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD) prone to exacerbations with nontypeable Haemophilus influenzae have impaired responses to lipoprotein P6. We hypothesized that an underlying immunosuppressive network could be responsible for the defective antibacterial immunity observed in these patients. We evaluated T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and exhausted T effector cells (programmed death 1 [PD-1](+)) in patients with COPD, because these cells are known to play a pivotal role in suppressing immune responses.

Objectives: We performed an in-depth characterization of Tregs, T effector cells, and MDSC in COPD and correlated their levels and function with disease severity.

Methods: Treg, effector T cell, and MDSC frequency from patients with COPD and healthy subjects' PBMCs were analyzed by flow cytometry. Treg immunosuppressive capacity was measured by in vitro suppression assay. The frequency of interferon-? producing T cells and T-cell proliferation were measured after blocking CTLA-4 and PD-1. Plasma proinflammatory and immunosuppressive cytokine levels were measured.

Measurements And Main Results: Significantly increased levels of Tregs, MDSC, and PD-1(+) exhausted effector T cells were present in patients with COPD compared with healthy subjects. Tregs from patients with COPD suppressed P6-specific T-cell proliferation to a greater extent than Tregs from healthy subjects. Plasma levels of Treg-generated cytokines, IL-10, and transforming growth factor-? were elevated. Blockade of CTLA-4 resulted in significant augmentation of T-cell IFN-? production in patients with COPD.

Conclusions: Functionally suppressive Tregs, MDSCs, and exhausted PD-1(+) T cells contribute to effector T-cell dysfunction in COPD.

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http://dx.doi.org/10.1164/rccm.201312-2293OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226027PMC
July 2014
16 Reads
88 Citations
15.250 Impact Factor

High immunosuppressive burden in advanced hepatocellular carcinoma patients: Can effector functions be restored?

Oncoimmunology 2013 Jul 30;2(7):e24679. Epub 2013 Apr 30.

Department of Immunology; Roswell Park Cancer Institute; Buffalo, NY USA.

The accumulation of immunosuppressive cells and exhausted effector T cells highlight an important immune dysfunction in advanced stage hepatocellular carcinoma (HCC) patients. These cells significantly hamper the efficacy immunotherapies and facilitate HCC progression. We have recently demonstrated that the multipronged depletion of immunosuppressive cells potentially restores effector T-cell function in HCC.

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http://dx.doi.org/10.4161/onci.24679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782165PMC
July 2013
13 Reads
10 Citations
7.700 Impact Factor

Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality.

Cancer Res 2013 Apr 19;73(8):2435-44. Epub 2013 Feb 19.

Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

The extent to which T-cell-mediated immune surveillance is impaired in human cancer remains a question of major importance, given its potential impact on the development of generalized treatments of advanced disease where the highest degree of heterogeneity exists. Here, we report the first global analysis of immune dysfunction in patients with advanced hepatocellular carcinoma (HCC). Using multi-parameter fluorescence-activated cell sorting analysis, we quantified the cumulative frequency of regulatory T cells (Treg), exhausted CD4(+) helper T cells, and myeloid-derived suppressor cells (MDSC) to gain concurrent views on the overall level of immune dysfunction in these inoperable patients. We documented augmented numbers of Tregs, MDSC, PD-1(+)-exhausted T cells, and increased levels of immunosuppressive cytokines in patients with HCC, compared with normal controls, revealing a network of potential mechanisms of immune dysregulation in patients with HCC. In dampening T-cell-mediated antitumor immunity, we hypothesized that these processes may facilitate HCC progression and thwart the efficacy of immunotherapeutic interventions. In testing this hypothesis, we showed that combined regimens to deplete Tregs, MDSC, and PD-1(+) T cells in patients with advanced HCC restored production of granzyme B by CD8(+) T cells, reaching levels observed in normal controls and also modestly increased the number of IFN-? producing CD4(+) T cells. These clinical findings encourage efforts to restore T-cell function in patients with advanced stage disease by highlighting combined approaches to deplete endogenous suppressor cell populations that can also expand effector T-cell populations.



https://www.roswellpark.org/media/news/liver-cancers-armed-many-strategies-evading-immune-response

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http://dx.doi.org/10.1158/0008-5472.CAN-12-3381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645275PMC
April 2013
16 Reads
180 Citations
9.329 Impact Factor

Induction of specific human cytotoxic T cells using dendritic cells transduced with an adenovector encoding rat epidermal growth factor receptor 2.

Int J Oncol 2011 Oct 14;39(4):907-13. Epub 2011 Jul 14.

Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.

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http://dx.doi.org/10.3892/ijo.2011.1124DOI Listing
October 2011
6 Reads
5 Citations
3.300 Impact Factor

Transgenic plant-based oral vaccines.

Immunol Invest 2010 ;39(4-5):468-82

Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Oral vaccines offer significant advantages over needle-based vaccines for achieving universal childhood vaccination goals. The expression of vaccine antigens in transgenic plants has the potential to provide a convenient, safe approach for oral vaccination and thus a feasible alternative to traditional parenteral vaccines. Many developments in the field have ushered in improvements such as enhanced protein antigen expression for the use of plants as factories for vaccine production, and facilitated studies pertaining to immunogenicity of candidate vaccines. Oral delivery of plant-based vaccines offers the benefit of antigen protection within the harsh intestinal environment. Within the gut, mucosal immune cells are poised to respond to pathogens, but can also be exploited to elicit protective immune responses to oral vaccines. Inclusion of mucosal adjuvants during immunization with the vaccine antigen has been an important step towards the success of plant-based vaccines. This review discusses the mechanisms that control mucosal immune responses and highlights some of the studies and the results achieved following immunization with transgenic plants.

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http://dx.doi.org/10.3109/08820131003622643DOI Listing
August 2010
15 Reads
25 Citations
1.903 Impact Factor

Generation of in vitro B-CLL specific HLA class I restricted CTL responses using autologous dendritic cells pulsed with necrotic tumor lysate.

Leuk Lymphoma 2006 Feb;47(2):297-306

Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5.

New approaches in the treatment of chronic B lymphocytic leukemia (B-CLL) have led to improved clinical response rates. In this setting there is a need to evaluate novel therapeutic approaches that aim to eradicate minimal residual B-CLL cells following an initial favorable response. The use of tumor lysate-pulsed dendritic cells (DC) represents a potentially important development in the field of cancer vaccination. B-CLL is ideally suited for DC-based vaccination since tumor cells are readily available (peripheral blood) and both known (tumor idiotype) and unknown antigens can be exploited to stimulate immune responses. In the current study we have evaluated the ability to stimulate in vitro autologous immune reactivity against target B-CLL cells using autologous DCs pulsed with B-CLL tumor lysate. Enhanced specific T cell IFN-gamma expression was detected in 9 of 14 patients evaluated. These responses were specific with increased levels of IFN-gamma mRNA measurable in T-cells stimulated with NC-DCs and not unpulsed DCs or DCs pulsed with normal B cell lysate. CTLs demonstrating increased levels of IFN-gamma mRNA also lysed autologous B-CLL targets cells in an MHC class 1-restricted manner by (51)chromium release assay. Priming target leukemic cells with CD40 ligand and IL-4 enhanced CTL killing. The effector CTL displayed negligible toxicity against NK susceptible target cells K-562 and spared CD19(+)CD5(-) normal B cells in cytotoxicity assays. The specificity of the CTL response was confirmed by blocking HLA class I molecules and cold target inhibition assays.

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http://dx.doi.org/10.1080/10428190500301231DOI Listing
February 2006
7 Reads
23 Citations
3.300 Impact Factor

Recent advances in immunotherapy of B-CLL using ex vivo modified dendritic cells.

Hematology 2005 Jun;10(3):189-203

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ont., Canada, L8N 3Z5 2.

Chronic lymphocytic leukemia (CLL) results from the relentless accumulation of small mature, slowly dividing, monoclonal B-lymphocytes. The clinical course is heterogeneous, some patients with aggressive form of the disease progressing rapidly with early death while others exhibit a more stable, possibly, non-progressing indolent type of the disease lasting many years. Despite progress in modern treatment modalities, relapse invariably occurs and disease still remains incurable. The clinical management of CLL is therefore challenging and considerable effort has been directed towards novel therapeutic strategies aimed at reducing minimal residual disease which can increase remission duration. Recent insight into the role of dendritic cells (DCs) as pivotal antigen presenting cells that initiate immune responses may provide the basis for generating more specific and effective immune responses. Ex-vivo modified and monocyte-derived DCs represents a promising approach within the context of CLL. However, understanding the relationship between DCs and the cellular immune response is crucial in devising strategies for manipulating immune responses. After a brief survey of general properties of DCs, this review focuses on the different approaches exploiting monocyte-derived DCs in CLL, which may help to design novel strategies for phase-I clinical trials.

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http://dx.doi.org/10.1080/10245330500094870DOI Listing
June 2005
4 Reads
3 Citations
1.189 Impact Factor

Augmentation of murine natural killer cell and antibody dependent cellular cytotoxicity activities by Phyllanthus emblica, a new immunomodulator.

J Ethnopharmacol 1994 Aug;44(1):55-60

Department of Biochemistry, Indian Institute of Science, Bangalore.

When administered orally, Phyllanthus emblica, an excellent source of vitamin C (ascorbate), has been found to enhance natural killer (NK) cell activity and antibody dependent cellular cytotoxicity (ADCC) in syngeneic BALB/c mice, bearing Dalton's lymphoma ascites (DLA) tumor. P. emblica elicited a 2-fold increase in splenic NK cell activity on day 3 post tumor inoculation. Enhanced activity was highly significant on days 3, 5, 7 and 9 after tumor inoculation with respect to the untreated tumor bearing control. A significant enhancement in ADCC was documented on days 3, 7, 9, 11 and 13 in drug treated mice as compared to the control. An increase in life span (ILS) of 35% was recorded in tumor bearing mice treated with P. emblica. This increased survival was completely abrogated when NK cell and killer (K) cell activities were depleted either by cyclophosphamide or anti-asialo-GM1 antibody treatment. These results indicate: (a) an absolute requirement for a functional NK cell or K cell population in order that P. emblica can exert its effect on tumor bearing animals, and (b) the antitumor activity of P. emblica is mediated primarily through the ability of the drug to augment natural cell mediated cytotoxicity.

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http://dx.doi.org/10.1016/0378-8741(94)90099-xDOI Listing
August 1994
184 Reads
110 Citations
3.200 Impact Factor

Modulatory potency of drum stick lectin on the host defense system

Journal of Experimental & Clinical Cancer Research Jan 1994 13(3):205-209

Journal of Experimental & Clinical Cancer Research 13(3):205-209

Abstract
The immunomodulatory effect of a glucosamine specific lectin from drum stick (Moringa oleifera) (MOL) on selected immunological parameters was studied in Balb/c mice. The effect of MOL on splenic lymphoid cells tested in vitro by (3H) thymidine incorporation assay revealed the mitogenic property of MOL towards lymphocytes even at low concentrations (9 to 15 μg/ml). Further, MOL was shown to exert its modulatory effect in vivo on immune profiles of tumor bearing mice as reflected on natural killer cell mediated cytotoxicity (NKCMC) and antibody dependent cellular cytotoxicity (ADCC). These effects were assessed at various time points of tumor growth against radiolabelled YAC-1 cells and antibody coated sheep red blood cells (SRBC) as respective targets, in a short term 51Cr release assay. A single dose of MOL intraperitoneally resulted in a significant enhancement in NKCMC within 96 hrs. ADCC responses were seen to have peaks on days 9 and 17 following the lectin administration.
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January 1994

39 Citations

Impact Factor 3.300

14 Reads

Top co-authors

Yasmin Thanavala
Yasmin Thanavala

Roswell Park Cancer Institute

10
Austin Miller
Austin Miller

Roswell Park Cancer Institute

6
Renuka Iyer
Renuka Iyer

Roswell Park Cancer Institute

5
Amit A Lugade
Amit A Lugade

Roswell Park Cancer Institute

3
Kalathil Suresh
Kalathil Suresh

McMaster University

3
Tariq A Bhat
Tariq A Bhat

School of Life Sciences

3
Jack Gauldie
Jack Gauldie

McMaster University

3
Ronan Foley
Ronan Foley

McMaster University

3
Elizabeth Scheid
Elizabeth Scheid

McMaster University

2