Elucidating the role of CD8A:MYD88 on CD8 T cell fate in response to solid tumors
Active Project Grant Awarded Last action
- Award ID
- F31CA301529
- Recipient
-
The Regents Of The University Of Colorado UEI MW8JHK6ZYEX8 Part of The Regents Of The University Of Colorado
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $38,798
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Place of performance
- Aurora, CO 80045, USA
Award details come from USAspending.gov.
Description
- Abstract
- Antigen persistence limits the efficacy and durability of cancer immunotherapies. Chronically stimulated CD8 T cells fail to develop immunological memory and instead undergo a terminal differentiation process known as exhaustion. Terminally exhausted T cells are dysfunctional and fail to control tumor growth. Conversely, progenitor T cells exhibit stem/memory features of self-renewal, long-term persistence, and are essential to maintaining the antitumor response. In fact, development of T cell therapies that support a stem/memory-like state have been shown to improve the functional longevity of tumor-specific T cells. Therefore, identifying innovative strategies to oppose exhaustion while fostering stem/memory cell states is critical to improving T cell therapies. The davila lab has developed a CO-receptor linking CD8 to the myeloid differentiation response protein-88 (MYD88). Downstream of IL-1/-18/-33 and toll-like receptor (TLR) families, MYD88 signal transduction induces transcription factor (TF) activity to regulate cell function, proliferation, and differentiation. Numerous studies have established the robust CO-stimulatory effects induced by TLR/MYD88 in T cells. Importantly, the davila lab has reported that CD8:MYD88 T cells exhibit enhanced antitumor activity and appear to restrain exhaustion; however, the mechanism(S) linking CD8:MYD88 with exhaustion has not been investigated. Thus, the objective of this proposal is to elucidate how CD8 :MYD88 T cells oppose terminal exhaustion. Preliminary work in the lab revealed that CD8:MYD88 T cells downregulate expression of inhibitory receptors characterized in exhausted T cells at both the protein and transcriptional levels. Further, CD8:MYD88 tumor infiltrating lymphocytes (TIL) exhibited a stem-like phenotype and expressed significantly greater levels of TCF1. Together, this suggests that expression of CD8:MYD88 may restrain exhaustion while concurrently supporting stemness programs in CD8 T cells. Interestingly, RNA-SEQ results showed that CD8:MYD88 T cells expressed unconventional TFS, POU2F2 (OCT2) and POU2AF1 (OCAB), which function in innate cells as epigenetic regulators of cell fate. Thus, we hypothesize that expression of CD8:MYD88 in T cells induces a unique transcriptional regulatory network that restrains terminal exhaustion and simultaneously supports a stem-like state, leading to sustained antitumor activity and development of immunological memory. To test this hypothesis, experiments in aim 1 will elucidate the molecular landscape induced in CD8:MYD88 TIL by integrated atac- and single cell RNA-SEQ. Further, aim 1 will determine the functional relevance of TFS OCT2/OCAB in regulating CD8 T cell exhaustion. Aim 2 will investigate the stemness potential of CD8:MYD88 T cells by assessing self-renewal and antigen-independent persistence. Studies proposed in aim 2 will also determine if CD8:MYD88 T cells can develop a functional memory response upon tumor rechallenge. Together, this proposal may identify novel impacts of CD8:MYD88 expression on T cell fate and characterize a previously undescribed role of OCT2/OCAB in regulating CD8 T cell exhaustion to improve future T cell immunotherapies.
Quick answers
Who received award F31CA301529?
F31CA301529 was awarded to The Regents Of The University Of Colorado by National Cancer Institute (National Institutes of Health) on December 1, 2026.
How much is award F31CA301529 worth?
$38,798 has been obligated on F31CA301529.
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