Squamous cell carcinomas of the head and neck (HNSCC) are among the most immunosuppressive human tumors. Tumor-induced and therapy-induced immune suppression may be responsible for disease recurrence seen in over 60% of SCCHN patients receiving curative therapies. Our data indicate that adenosine and PGE2 are among the major immunosuppressive factors in HNSCC. Not only the tumor but also regulatory T cells (Treg) produce these factors, and adaptive Treg accumulate in the tumor microenvironment during tumor progression. Their frequency and function increase after chemoradiation (CRT) and remain elevated for months, potentially contributing to tumor recurrence. In this proposal, we test the hypothesis that restoration of anti-tumor immunity in the microenvironment of HNSCC can be achieved in vitro and in vivo by down-regulating Treg and enhancing Teffector cell (Teff) functions using pharmacologic agents which target the adenosine/PGE2 pathway. In three aims, we propose to: (1) conduct a prospective non-therapeutic longitudinal study in HNSCC patients treated with surgery and CRT to ask whether persistent immune suppression and enhanced activity of the adenosine/PGE2 pathway after CRT contribute to the tumor recurrence;(2) study in vitro effects of the pharmacological blockade of the adenosine/PGE2 pathway on Treg-mediated suppression and potentially concomitant restoration of anti-tumor functions of Teff;and (3) show that metabolic silencing of the adenylyl cyclase and stimulation of phosphodiesterase activity in Teff in vivo promotes anti-tumor immune responses to a multi-epitope vaccine, induces tumor rejection and prolongs survival of 4NQO mice with oral carcinoma. These pre-clinical studies are designed to demonstrate that persistent accumulations of Treg in the human tumor microenvironment are associated with tumor progression and that the pharmacological blockade of a common immunosuppressive pathway alone or in combination with conventional cancer therapy silences Treg, restores anti-tumor immunity and inhibits tumor growth. The potential of this new combinatorial therapy for re-establishing effective anti-tumor immunity following CRT in HNSCC is expected to provide the rationale for its translation to the clinic.

Public Health Relevance

The immuno-suppressive microenvironment of human HNSCC is characterized by accumulations of Treg and dysfunction of anti-tumor effector T cells. Chemoradiation (CRT) increases the adaptive Treg frequency and functions. Adenosine/PGE2 produced by these cells might contribute to poor anti-tumor immunity after therapy and to cancer recurrence. A prospective longitudinal clinical study in HNSCC patients receiving SOC therapy will determine whether post-therapy immune suppression, in part mediated by Treg, can be linked to tumor recurrence. Pharmacological silencing of the adenosine/PGE2 pathway in conjunction with conventional therapies is expected to restore anti-tumor effector functions and prevent recurrence. This pre-clinical project will investigate biologic, mechanistic and therapeutic consequences of the blockade in vitro and in a mouse model of oral carcinoma in hope of restoring anti-tumor functions of immune cells and thus prevent recurrence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA168628-01A1
Application #
8502828
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
2013-05-13
Project End
2018-04-30
Budget Start
2013-05-13
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$316,438
Indirect Cost
$108,938
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Muller-Haegele, Sylvia; Muller, Laurent; Whiteside, Theresa L (2014) Immunoregulatory activity of adenosine and its role in human cancer progression. Expert Rev Clin Immunol 10:897-914
Schuler, P J; Saze, Z; Hong, C-S et al. (2014) Human CD4+ CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells. Clin Exp Immunol 177:531-43
Whiteside, Theresa L (2014) Induced regulatory T cells in inhibitory microenvironments created by cancer. Expert Opin Biol Ther 14:1411-25
Muller, Laurent; Hong, Chang-Sook; Stolz, Donna B et al. (2014) Isolation of biologically-active exosomes from human plasma. J Immunol Methods 411:55-65
Whiteside, Theresa L (2014) Clinical Impact of Regulatory T cells (Treg) in Cancer and HIV. Cancer Microenviron :
Whiteside, Theresa L (2014) Regulatory T cell subsets in human cancer: are they regulating for or against tumor progression? Cancer Immunol Immunother 63:67-72
Hong, Chang Sook; Muller, Laurent; Boyiadzis, Michael et al. (2014) Isolation and characterization of CD34+ blast-derived exosomes in acute myeloid leukemia. PLoS One 9:e103310