Publications by authors named "Jeetendra Kumar"

5 Publications

  • Page 1 of 1

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

Cell Rep 2021 Nov;37(8):110047

University of Toronto Musculoskeletal Oncology Unit, Sinai Health System; Department of Surgery, University of Toronto, Toronto, ON, Canada.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.
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November 2021

Clinical profile and risk factors for mortality among COVID-19 inpatients at a tertiary care centre in Bengaluru, India.

Monaldi Arch Chest Dis 2021 May 17;91(3). Epub 2021 May 17.

ESIC Medical College & Post Graduate Institute of Medical Sciences and Research, Rajajinagar, Bengaluru.

COVID-19 is an emerging viral disease affecting more than 200 countries worldwide and it present with varied clinical profile throughout the world. Without effective drugs to cure COVID-19, early identification and control of risk factors are important measures to combat COVID-19.  This study was conducted to determine the clinical profile and risk factors associated with mortality among COVID-19 patients in a tertiary care hospital in South India. This record-based longitudinal study was conducted by reviewing the case records of COVID-19 patients admitted for treatment from June 2020 to September 2020 in a tertiary care centre in South India. The clinical details, discharge/death details, were collected and entered in MS Excel. Potential risk factors for COVID-19 mortality were analysed using univariate binomial logistic regression, generalized linear models (GLM) with Poisson distribution. Survival curves were made using the Kaplan-Meier method. Log-rank test was used to test the equality of survivor functions between the groups. Out of 854 COVID-19 patients, 56.6% were men and the mean (standard deviation) age was 45.3(17.2) years. The median survival time was significantly lesser in male COVID-19 patients (16 days) as compared to female patients (20 days). Increasing age, male gender, patients presenting with symptoms of fever, cough, breathlessness, smoking, alcohol consumption, comorbidities were significantly associated with mortality among COVID-19 patients. Patients with older age, male gender, breathlessness, fever, cough, smoking and alcohol and comorbidities need careful observation and early intervention.  Public health campaigns aimed at reducing the prevalence of risk factors like diabetes, hypertension, smoking and alcohol use are also needed.
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May 2021

Pediatric tolerogenic DCs expressing CD4 and immunoglobulin-like transcript receptor (ILT)-4 secrete IL-10 in response to Fc and adenosine.

Eur J Immunol 2018 03 15;48(3):482-491. Epub 2018 Jan 15.

La Jolla Institute for Allergy and Immunology, Division of Developmental Immunology, Athena Circle, La Jolla, CA, USA.

We characterized a novel population of tolerogenic myeloid dendritic cells (tmDCs) defined as CD11c CD11b CD14 CD4 and immunoglobulin-like transcript receptor (ILT)-4 that are significantly more abundant in the circulation of infants and young children than in adults. TmDCs secrete the immunosuppressive lymphokine interleukin (IL)-10 when stimulated with the heavy constant region of immunoglobulins (Fc) and express high levels of the adenosine A receptor (A R), which, when activated by adenosine, inhibits the release of pro-inflammatory cytokines from most immune cells. Here we show that stimulation of the A R on tmDCs by regadenoson or N-ethylcarboxamidoadenosine (NECA) rapidly increases cyclic AMP accumulation and enhances IL-10 production under Fc stimulatory conditions. In co-culture experiments, tmDCs inhibit the differentiation of naïve T cells to a pro-inflammatory phenotype. In conclusion, although DCs are classically viewed as antigen presenting cells that activate T cells, we show an independent role of tmDCs in pediatric immune regulation that may be important for suppressing T cell responses to neoantigens in infants and young children.
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March 2018

Umbilical cord blood-derived CD11c(+) dendritic cells could serve as an alternative allogeneic source of dendritic cells for cancer immunotherapy.

Stem Cell Res Ther 2015 Sep 25;6:184. Epub 2015 Sep 25.

Stem Cell Laboratory, National Centre for Cell Science, Ganeshkhind, Pune, 411007, India.

Introduction: Allogenic dendritic cells (DCs) generated from healthy donors, who are complete or partially HLA-matched, have been used for clinical trials. One of the sources for allogenic DCs is umbilical cord blood (UCB) cells. However, as far as cord blood cells are concerned, looking at their naïve nature, there is a concern as to whether the DCs generated from them will have enough potential to elicit a proper T cell response. For this, we compared CD11c(+) UCB-DCs/ Cytotoxic T lymphocytes (CTLs) with the conventional source, i.e. peripheral blood (PBL) monocyte DCs/CTLs, using various parameters.

Methods: CD11c(+) DCs generated from the two sources were compared morphologically, phenotypically and functionally. Functional assays included antigen uptake, chemotactic migration and MLR (mixed lymphocyte reaction). The CTLs generated were examined for the activation markers, granzyme A & granzyme B, and IFN-γ secretion. MUC1 (STAPPVHNV) peptide-specific CTLs were quantified by Streptamer staining. In vitro CTL activity was assessed by their efficiency in killing MCF-7 cells. For in vivo CTL assay, a xenograft of MCF-7-luc-F5 cells in female NOD/SCID mice was employed. Regression of tumors in mice was monitored using an in vivo imaging system before and after ten days of CTL infusion. Statistical analysis of all the experiments between the two groups was evaluated by one-way ANOVA.

Results: The CD11c(+) DCs from the two sources were morphologically and phenotypically similar. Their capacity to uptake antigen, migration towards CCL-19 and MLR activity were equivalent. UCB-CTLs had significantly higher levels of activation markers, number of MUC1 specific CTLs, IFN-γ secretion and IL-12p70/IL-10 ratio than that of PBL-CTLs. Hematoxylin and Eosin-stained tumor sections showed T cell infiltration, which was further confirmed by immunofluorescence staining. In vivo CTL activity was found to be similar with the two sources.

Conclusions: Our data demonstrate that CD11c(+) UCB-DCs/CTLs are as potent as standard CD11c(+) PBL-DC/CTLs and could therefore be used as an allogenic source for therapeutic purposes. The findings of this study could help in taking us one step closer towards the personalized therapy using DC based cancer vaccines.
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September 2015

Exogenous addition of arachidonic acid to the culture media enhances the functionality of dendritic cells for their possible use in cancer immunotherapy.

PLoS One 2014 4;9(11):e111759. Epub 2014 Nov 4.

Stem Cell Lab., National Centre for Cell Science, Ganeshkhind, Pune, India.

The development of dendritic cell based vaccines is a promising approach in cancer immunotherapy. For their successful use in the clinics, the propagation and functionality of DCs is crucial. We earlier established a two-step method for the large scale generation of DCs from umbilical cord blood derived MNCs/CD34(+) cells. This work aims at improving their functionality based on the following observations: in vitro generated DCs can be less efficient in migration and other functional activities due to lower eicosanoid levels. The production of eicosanoids from Arachidonic Acid (AA) can be hampered due to suppression of the enzyme phospholipase A2 by IL-4, an essential cytokine required for the differentiation of DCs. We hypothesized that exogenous addition of AA to the culture media during DC generation may result in DCs with improved functionality. DCs were generated with and without AA. The two DC sets were compared by phenotypic analysis, morphology and functional assays like antigen uptake, MLR, CTL assay and in vitro and in vivo migration. Though there were no differences between the two types of DCs in terms of morphology, phenotype and antigen uptake, AA(+) DCs exhibited an enhanced in vitro and in vivo migration, T cell stimulatory capacity, CTL activity and significantly higher transcript levels of COX-2. AA(+) DCs also show a favorable Th1 cytokine profile than AA- DCs. Thus addition of AA to the culture media is skewing the DCs towards the secretion of more IL-12 and less of IL-10 along with the restoration of eicosanoids levels in a COX-2 mediated pathway thereby enhancing the functionality of these cells to be used as a potent cellular vaccine. Taken together, these findings will be helpful in the better contriving of DC based vaccines for cancer immunotherapy.
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June 2015