Overcoming CD4 T cell dysfunction in acute lymphoblastic leukemia
Active Project Grant Awarded Last action
- Award ID
- F31CA306005
- Recipient
-
Regents Of The University Of Minnesota UEI KABJZBBJ4B54
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $38,277
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Place of performance
- Minnesota, USA
Award details come from USAspending.gov.
Description
- Abstract
- Relapsed acute lymphoblastic leukemia (all) is the 2ND leading cause of cancer death in children. Current treatments are very effective at inducing remission but preventing relapse remains a significant clinical problem. Recent studies have shown that the presence of increased numbers of CD4+TIM3+ T cells is the best predictor for relapse. However, what role CD4+ T cells play in leukemia immunosurveillance and how CD4 T cell dysfunction impacts this process remains a key GAP in our knowledge. Thus, elucidating how CD4 T cell dysfunction in B-all contributes to relapse and how this can be reversed will provide key insights into how leukemia induces immune escape mechanisms and inform strategies to clear residual leukemia thereby inducing durable remission. To understand mechanisms of leukemia-induced immune tolerance, I will use a BCR-ABL+ model of B-all. Remission can be induced with the tyrosine kinase inhibitor (TKI) nilotinib, although virtually all mice relapse within several weeks. We recently demonstrated that relapse can be prevented by the combination of nilotinib plus anti- PDL1. Preliminary data shows that leukemia promotes the differentiation of immunosuppressive IL10+ type I regulatory (TR1) T cells; TR1 differentiation is enhanced by nilotinib treatment, which likely drives relapse. In contrast, the combination of nilotinib plus anti-PDL1 treatment blocks TR1 differentiation and instead promotes differentiation of TH1 effector cells that correlates with improved survival of leukemia-bearing mice. However, how leukemia induces TR1 differentiation and how nilotinib plus anti-PDL1 reverses this effect remains unknown. I hypothesize that in B- all, mhcii+ leukemia cells expand CD4+ TR1 cells via direct antigen presentation and the secretion of suppressive cytokines. I further propose that TR1 induction occurs in a spatially restricted niche that promotes relapse. Finally, I hypothesize that anti-PDL1 disrupts this immunosuppressive niche, driving the differentiation of a TH1 effector population that eradicates residual leukemia cells thereby preventing relapse. I will address these hypotheses in two aims. AIM1 will identify the mechanisms by which leukemia induces a tolerogenic microenvironment, while aim 2 will elucidate how dual treatment using tkis and anti-PD-L1 checkpoint blockade drives an effective CD4+ T cell response. These studies will further our understanding of how B- all induces immune tolerance and how this can be reversed. These studies will also promote my training by developing my expertise in animal models of disease, flow cytometry, genetic engineering, microscopy, and bioinformatics. These skills will promote my scientific development as I become a cancer immunologist and seek to lead a lab developing cancer immunotherapies.
Quick answers
Who received award F31CA306005?
F31CA306005 was awarded to Regents Of The University Of Minnesota by National Cancer Institute (National Institutes of Health) on February 27, 2027.
How much is award F31CA306005 worth?
$38,277 has been obligated on F31CA306005.
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