Advanced melanoma is a major target of cancer immunotherapy research due to its poor survival rate even with recent treatment advances. Current strategies focus on CD8 T cells which enter a dysfunctional state in the tumor microenvironment. Recent studies have found that intratumoral CD8 T cells consist of a heterogeneous population of memory-like progenitor, effector and terminally exhausted cells that exhibit differing functional and self-renewal capacities. However, the cellular and molecular processes involved in the differentiation of these subsets within melanoma is not well understood. Exploring the intricacies of CD8 T cell differentiation towards an effector profile can identify novel immunotherapeutic targets. Thus, the long-term goal of this project is to elucidate the mechanisms regulating effector CD8 T cell differentiation and function in melanoma. CD4 T cell production of cytokines provide help to CD8 T cells. Recent studies have uncovered the cytokine IL- 21 as a critical signal produced by CD4 T cells to help promote CD8 T cell maintenance in chronic infection. However, the direct effects of IL-21 produced by CD4 T cells on CD8 T cell differentiation and function in cancer remains unknown. Preliminary data presented in this proposal suggest that IL-21 producing CD4 T cells induce an effective antitumor response dependent on CD8 T cells. Additionally, it has been previously found that IL-21 signaling induces the transcription factor BATF, which is known to cooperatively bind with IRF4 to induce changes in the chromatin landscape. This has led to the hypothesis that the IL-21-BATF pathway enhances melanoma-infiltrating effector CX3CR1+ CD8 T cells and their function via BATF-IRF4 mediated transcriptional regulation.
Aim 1 will determine if adoptively transferred IL-21-producing CD4 T cells enhance effector CX3CR1+ CD8 T cell differentiation. The effect of CD4 T cell-derived IL-21 on CD8 T cell differentiation and function will be determined in vivo. Then, it will be determined if IL-21R signaling is intrinsically necessary for the CD8 T cell response to IL-21 producing CD4 T cell help.
Aim 2 will investigate the mechanism of BATF-mediated tumor-infiltrating CD8 T cell differentiation. These experiments will determine if BATF-IRF4 interaction is necessary to promote tumor-infiltrating CX3CR1+ CD8 T cells. Furthermore, changes in BATF-mediated chromatin accessibility in CD8 T cell differentiation and function will be assessed. This proposal will help in understanding how CD8 T cells differentiate and function in melanoma. This is in line with the mission of NCI, as the results of this project could lead to the identification of BATF as a novel therapeutic mechanism to enhance effector CD8 T cell differentiation to fight cancer.

Public Health Relevance

Advanced melanoma remains resistant to treatment; therefore, recent cancer immunotherapy research aims at enhancing the immune response against cancer. The cytokine IL-21, produced by CD4 T cells, may play a critical role in promoting functional effector CD8 T cells and preventing their exhaustion. Thus, the overall goal of this project is to dissect the mechanism by which CD8 T cells limit exhaustion and promote antitumor function, as this can help to identify novel cancer therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30CA246920-01
Application #
9906544
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bian, Yansong
Project Start
2020-01-01
Project End
2023-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Versiti Wisconsin, Inc.
Department
Type
DUNS #
057163172
City
Milwaukee
State
WI
Country
United States
Zip Code
53233