Current Research

Our laboratory studies the cellular and molecular mechanisms involved in the requirements for the generation of distinct murine and human T lymphocyte lineages. We use this knowledge to generate polyfunctional and durable memory T cells that mediate potent responses against established tumors.

Differentiation of helper T cell subsets
"Differentiation of helper T cell subsets from naïve CD4+T cells mediated by cytokines and co-signals. Th1, Th2, Th17, Th9, Th22, follicular T helper cells (TFH) and regulatory T cells (Treg) are induced via various cytokines and co-stimulatory molecules produced by antigen-presenting cells, such as dendritic cells and macrophages. These distinct subsets regulate immune response to foreign, self and tumor antigens."

From Majchrzak et al., 2016

Our studies on costimulatory molecules CD28 and ICOS are focused on how modulate T cells towards a unique helper or cytotoxic lineage. We are characterizing the transcription factors involved in lineage commitment, plasticity and in regulation of CD4 and CD8 gene expression, with emphasis on the roles of transcription factors RORgt, T-bet, beta-catenin and FoxP3 and the mechanisms for establishing epigenetic programs in maturing tumor-specific T cell subsets. Our studies on both mouse and human T cells have led to the discovery of a costimulatory molecule, the inducible costimulatory molecule ICOS, that is required for the differentiation of highly inflammatory Th17 cells. We are investigating how ICOS signaling and interactions between transcription factors influence T helper cell differentiation towards the Th17 versus the anti-inflammatory regulatory T cell lineages in an adoptive cell transfer mouse and human models of cancer.

ICOS signaling
ICOS sends the right signals to human Th17 cells to break self-tolerance to tumors.

Paulos, CM et. al., Science Transl Med. 2 (55):55ra78 (2010) (PDF)

We are also further investigating Th17 cells as a more potent CD4+ subset for adoptive immunotherapy:

Antitumor efficacy of Th17 cells
"Human Th17 cells retain antitumor efficacy after 2 weeks of ex vivo expansion while Th1 cells do not."

From Bowers et al., 2017

Another distinct area of interest of our laboratory is in elucidating the mechanisms by which chemotherapy and or total body irradiation is effective in improving T-cell based immunotherapies. We are employing genetic and cell biological approaches to study the mechanism for enhancement of mouse and human Tumor-specific T cell function and proliferation by host preconditioning. We have found that chemotherapy dramatically alters the gut microbiota and that distinct antibiotics can differentially shape the antitumor properties of adoptive transferred and host immune cells to kill large tumors in mice. We are also developing mouse models to study the potential role of these genetically redirected cells in optimally preconditioned mice.

LPS augments antitumor response without lymphodepletion
"Long-term curative responses can be mediated in mice without lymphodepletion by depleting host CD4+T cells and activating APCs with TLR4 agonists LPS. "

From Nelson et al., 2015

Additionally, we are interested in using pharmacological drug combinations to instill durable anti-tumor T cell memory and activity:

Juicing Th17 cells
"ICOS-activated Th17 cells expanded in the presence of CAL-101 and indomethacin (Indo) possess a central memory phenotype (i.e., elevated CD62L expression). There are fewer regulatory properties (decreased FoxP3 expression) in this culture. Moreover, upon antigen recall in vivo dual-inhibited Th17 cells are multipotent (producing many cytokines) and exhibit elevated nuclear β-catenin and Tcf7 and augmented persistence in the host. These cells possess self-renewal and durable memory responses to solid tumors, enabling them to directly lyse established malignancies without help from endogenous immune cells. This finding shines light on new ways to repurpose FDA-approved drugs to augment cancer immunotherapy."

From Majchrzak et al., 2017

We have also recently identified a unique human CD4+ T cell subset that expresses high levels of the ectoenzyme CD26 with durable memory properties, called CD26high cells. Genetic redirection of CD26high cells with a chimeric antigen receptor or transgeneic TCR endows them with a robust capacity to eradicate large human tumors in NSG mice. We are actively investigating the mechanisms underlying the effectiveness and enhanced memory properties of these cells.

CD26high cells exhibit superior antitumor responses
“CD26 identifies three CD4+T cell subsets with distinct properties. CD26negT cells, despite their enhanced capacity to migrate, fail to regress tumors due to regulatory properties, decreased persistence, and increased sensitivity to cell death. CD26intand CD26highT cells exhibit similar antitumor activity, but have vastly different immunological properties. Despite their decreased migration, CD26intT cells are naive and capable of persisting long-term. CD26highT cells, despite their differentiated phenotype, exhibit several anti-apoptotic and stemness features, persist long-term, co-secrete multiple cytokines, and cytotoxic molecules and have a natural capacity to migrate towards various established solid tumors.”

From Bailey et al., 2017