Adoptive cell transfer (ACT) therapies for melanoma patients have failed to fulfill their therapeutic promise, largely due to the transfer of short-livd and terminally differentiated cells. A lack of means for developing long- lived T cell potency has hampered ACT advancement in the clinic. Understanding and manipulating the pathways that sustain T cell memory will potentially unlock durable responses to tumors. During my time in the Paulos lab, I have found that IL-17A/IFN-?/IL-22-producing CD4+ T cells that express enzymatically active CD26 on their cell surface - termed CD4+CD26high T cells - demonstrate exquisite, durable responses to tumors compared to Th1 or Th17 cells. Further investigation revealed that these cells potentially induce the expansion and engraftment of cytotoxic CD8+ T cells in vivo. Interestingly, we found that abrogating the enzymatic activity of CD26 on CD4+CD26high T cells with Alogliptin dramatically impaired their capacity to secrete the pro-inflammatory cytokines IL-17A, IL-22, IFN-? and IL-2, as well as the cytotoxin Granzyme B. Collectively, these data suggest that the enzymatic activity of CD26 plays a critical role in the function and cytotoxicity of CD4+CD26high T cells and could augment their antitumor properties in vivo. The importance of cytokine production by CD4+ T cells on the function, proliferation and cytotoxicity of CD8+ T cells has been well studied. Based on these reports, the loss of function induced by the inhibition of CD26 enzymatic activity could potentially reduce the ability of CD4+CD26high T cells to support CD8+ T cells. Given that the combined transfer of CD4+ and CD8+ T cells has proven efficacious in ACT therapy, it's important to deduce how the enzymatic activity of CD26 on CD4+CD26high T cells affects CD8+ T cells and if this activity can be targeted for enhanced therapy. We propose to gain further insight into CD4+CD26high T cell-mediated tumor immunity, hypothesizing that the enzymatic activity of CD26 plays a crucial role in the overall activity of human CD4+CD26highT cells as well as their ability to support CD8+ T cells (Aim 1), and that targeting this novel pathway is crucial for prolonging the efficacy of cancer immunotherapy (Aim 2). Overall, the proposed research is expected to demonstrate that manipulation of the CD26 pathway may sufficiently induce durable immunity against the growth and recurrence of advanced melanoma.

Public Health Relevance

We seek to understand how CD26 augments the antitumor response of CD4+CD26high T cells, which holds promise in the context of adoptive immunotherapy for mounting prolonged, robust responses against advanced malignancies. Our mechanistic studies on the enzymatic activity of CD26 and its role in T cell function, migration and cytotoxicity will allow us to harness this pathway to generate more potent, persistent T cells that elicit prolonged immune responses against cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA192787-02
Application #
9045382
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Korczak, Jeannette F
Project Start
2015-03-01
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Knochelmann, Hannah M; Dwyer, Connor J; Bailey, Stefanie R et al. (2018) When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell Mol Immunol 15:458-469
Bailey, Stefanie R; Nelson, Michelle H; Majchrzak, Kinga et al. (2017) Human CD26high T cells elicit tumor immunity against multiple malignancies via enhanced migration and persistence. Nat Commun 8:1961
Bowers, Jacob S; Majchrzak, Kinga; Nelson, Michelle H et al. (2017) PI3K? Inhibition Enhances the Antitumor Fitness of Adoptively Transferred CD8+ T Cells. Front Immunol 8:1221
Majchrzak, Kinga; Nelson, Michelle H; Bailey, Stefanie R et al. (2016) Exploiting IL-17-producing CD4+ and CD8+ T cells to improve cancer immunotherapy in the clinic. Cancer Immunol Immunother 65:247-59