Our long term goal is to develop a novel approach for treating established melanoma tumors by enhancing cytotoxic T cell responses towards weakly immunogenic and lowly expressed tumor antigens (TAgs) including neoantigens while simultaneously conferring T cells resistance to myeloid-derived suppressor cell (MDSC)? mediated suppression. In clinical trials, T cell-based immunotherapies have demonstrated tumor regression and increased survival rates. Yet despite these encouraging clinical results, durable antitumor responses are observed in only a subset of patients with advanced melanoma. This discrepancy stresses the need for more effective treatment strategies. T cell-based therapies are hindered in part by low T cell receptor (TCR) affinity and/or avidity and by the low expression of TAg on the tumor cell's surface. Additionally, the presence of MDSCs poses a major obstacle to generating effective and long-lived antitumor T cell responses. In our published and preliminary studies, activating MyD88 signaling in T cells, via toll like receptor engagement, augmented T cell responses and prolonged T cell survival. By fusing the CD8? (extracellular) to MyD88 (intracellular; CD8?:MyD88) molecule or by linking melanoma-reactive TCRs to MyD88 (TCR:MyD88) we have developed a novel platform that strongly activates MyD88 signaling in a TLR-independent, strictly TCR- dependent fashion. CD8?:MyD88 expression in T cells considerably amplifies responses to weak and suboptimal levels of TAg and in a TCR-dependent manner, and in preliminary studies has demonstrated the extraordinary property of differentiating MDSC's into cells that can enhance T cell responses. Importantly, the use of CD8? offers the unique feature in that it represents a `universal' approach to potentiating T cell responses, regardless of the patient's HLA type. Our central hypothesis is that T cells engineered to express a CD8?:MyD88 (or TCR:MyD88) will amplify TCR signals against a variety of weakly immunogenic or lowly expressed TAgs including neoantigens and reverse the suppressive activity of myeloid cell suppression, resulting in effective and long-lived antitumor responses.
Aim 1 is to determine the molecular mechanisms by which MyD88 activation in T cells augments TCR signals. Through in vitro studies of human and mouse cells, we will define the molecular interactions through which MyD88 signaling augments TCR responses to tumor antigens of varying affinities.
Aim 2 is determine the fate and antitumor efficacy of each CD8?:MyD88 and TCR:MyD88 T cells in mice with an established subcutaneous or intracranial melanoma tumor.
Aim 3 is to ascertain the in vivo significance and define the mechanism(s) through which MyD88 signaling in T cells reverses myeloid cell's suppressive function. These studies are clinically significant as they have the potential to offer mechanistic insights as to how TCR responses can be amplified and, novel strategies for inhibiting and/or reversing MDSC function.

Public Health Relevance

Our long term goal is to develop and characterize a novel strategy to enhance cytotoxic T cell responses towards weakly immunogenic and lowly expressed tumor antigens to treat established melanoma tumors in the brain and on the skin. This is an exciting approach that can potentially enhance the antitumor efficacy all forms of T cell-based cancer therapies or vaccines.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA207913-01A1
Application #
9309467
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$363,833
Indirect Cost
$128,152
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Kaczanowska, Sabina; Joseph, Ann Mary; Guo, Jitao et al. (2017) A Synthetic CD8?:MyD88 Coreceptor Enhances CD8+ T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens. Cancer Res 77:7049-7058
Tsai, Alexander K; Khan, Asra Y; Worgo, Christina E et al. (2017) A Multikinase and DNA-PK Inhibitor Combination Immunomodulates Melanomas, Suppresses Tumor Progression, and Enhances Immunotherapies. Cancer Immunol Res 5:790-803