Biology subjects

Premlal, A. L. R.

Publications and source records attributed to Premlal, A. L. R..

3 recordsLinked to original sources

bioRxiv2023

Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression

Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response of an aggressive low TMB squamous cell tumor to ICB could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4+ and CD8+ T cells. We found that, whereas vaccination with CD4+ or CD8+ NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1+ tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4+/CD8+ T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8+ T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. The concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.

immunology↗

bioRxiv2021

Transcriptomes and metabolism define mouse and human MAIT cell heterogeneity

Mucosal-associated invariant T (MAIT) cells are a subpopulation of T lymphocytes that respond to microbial metabolites. We performed single-cell RNA sequencing and metabolic analyses of MAIT cell subsets in thymus and peripheral tissues from mice and humans to define the heterogeneity and developmental pathway of these innate-like lymphocytes. We show that the predominant mouse subset, which produces IL-17 (MAIT17), and the subset that produces IFN{gamma} (MAIT1), have greatly different transcriptomes and metabolic states in the thymus and periphery. A splenic MAIT subset has a transcriptome similar to circulating lymphocytes, and in mice these also are found in recent thymic emigrants, suggesting partially mature cells emigrate from the thymus. Human MAIT cells are predominantly MAIT1 cells, but have a different metabolism from their mouse counterparts with increased fatty acid uptake and storage. Although mouse and human subsets are similar in thymus, in the periphery they diverge, likely reflecting environmental influences.

immunology↗

bioRxiv2020

Transcriptome and Chromatin Landscape of iNKT cells are Shaped by Subset Differentiation and Antigen Exposure

Invariant natural killer T cells (iNKT cells) differentiate into thymic and peripheral NKT1, NKT2 and NKT17 subsets. We determined if the gene programs associated with these thymic subsets were maintained in peripheral sites, the influence of tissue location, and if there were large-scale changes after antigen exposure. RNA-seq and ATAC-seq analyses showed that iNKT cells in any subset were similar, regardless of tissue location. Lung iNKT cell subsets possessed the most distinct location-specific features, shared with other innate lymphocytes in the lung, possibly consistent with increased activation. After antigenic stimulation, iNKT cells underwent chromatin and transcription changes leading to two populations: one similar to follicular helper T cells and the other like NK or effector cells. Phenotypic analysis indicated these changes were observed long-term, suggesting that iNKT cells gene programs are not fixed, but they are capable of chromatin remodeling after antigen to give rise to several new subsets.

immunology↗