The Department of Microbiology and Immunology is pleased to announce that Graduate Research Assistant, Kayla Reisch, has been awarded a National Research Service Award (F31CA314172) from the National Institutes of Health/National Cancer Institute. This one year award will provide financial support at the 2026 NRSA Stipend level for the project titled:  Deciphering the role of CD7 in modulating T cell responses within the tumor microenvironment.  Ms. Reisch is a member of the Ryan Zander  lab in the Department of Microbiology.

Project Summary:

Antigen persistence within the tumor microenvironment is often associated with CD8+ T cell “exhaustion”, a differentiation process characterized by upregulation of co-inhibitory receptors, such as PD-1, Lag3, and Tim3, and a loss of effector function. While immune checkpoint blockade (ICB) therapy has shown promise in the clinic, many patients still fail to respond to immunotherapy. This insufficient response has been linked to the fixed epigenetic programming of terminally exhausted CD8+ T cells, which prevents efficient reinvigoration upon treatment with checkpoint inhibitors. Notably, recent evidence shows that the pool of “exhausted” T cells is comprised of multiple heterogenous populations that vary in function. These include a TCF-1hi progenitor (Tprog) subset that transitions through an intermediate (Tint) state before developing into either terminally exhausted (Texterm) cells that express multiple co-inhibitory receptors, or cytolytic effector (Teff) cells that are critical for viral and/or tumor. Therefore, a better understanding of the molecular factors and transcriptional networks underlying this developmental bifurcation process should provide new opportunities to redirect Tprog cell differentiation towards protective Teff cells to improve immunotherapies aimed at treating chronic infections and/or cancer. Using single-cell RNA-sequencing, we have identified several previously unrecognized genes that may regulate the fate commitment of CD8+ T cells. We have gathered substantial preliminary data on our top gene candidate Cd7, highlighting its importance in regulating commitment to an exhausted CD8+ T cell fate. Our preliminary studies reveal: 1) high expression of Cd7 on Texterm during chronic infection; 2) elevated expression on exhausted tumor- infiltrating lymphocytes (TILs) isolated from murine and human tumors; 3) deletion of Cd7 in antigen-specific CD8 T cells reduced expression of exhaustion-programming TFs Tox and Eomes, enhanced the function and formation of protective Teff cells, and improved viral and tumor control. Therefore, the central hypothesis of this proposal is that CD7 signaling in the tumor microenvironment enhances TCR signaling strength in CD8+ TILs, eventually leading them to differentiate into terminally exhausted cells that have reduced effector function and no longer provide a durable immune response. Utilizing CRISPR-Cas9 deletion systems in antigen-specific CD8+ T cells, experiments proposed in Aim 1 will investigate how CD7 impacts the differentiation, transcriptional programming, and effector function of tumor specific TILs. Using an established in vitro exhaustion model system, Aim 2 will investigate how CD7 expression and stimulation via its ligands, impacts proximal TCR signaling pathways of human and murine CD8+ T cells. Collectively, at the end of the proposed studies, we will have gained a better understanding on how CD7 mechanistically functions to program CD8+ T cell dysfunction during cancer. Additionally, we believe this research has the potential to lead to the discovery of a novel immune checkpoint that can be targeted to promote durable Teff cell responses in multiple malignancies.