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 #
5R01CA168628-02
Application #
8661142
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
2014-05-01
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Whiteside, Theresa L (2017) The effect of tumor-derived exosomes on immune regulation and cancer immunotherapy. Future Oncol 13:2583-2592
Ludwig, Sonja; Floros, Theofanis; Theodoraki, Marie-Nicole et al. (2017) Suppression of Lymphocyte Functions by Plasma Exosomes Correlates with Disease Activity in Patients with Head and Neck Cancer. Clin Cancer Res 23:4843-4854
Whiteside, T L (2017) Exosomes carrying immunoinhibitory proteins and their role in cancer. Clin Exp Immunol 189:259-267
Whiteside, T L; Boyiadzis, M (2017) Response commentary: exosomes vs microvesicles in hematological malignancies. Leukemia 31:2277
Hong, Chang-Sook; Sharma, Priyanka; Yerneni, Saigopalakrishna S et al. (2017) Circulating exosomes carrying an immunosuppressive cargo interfere with cellular immunotherapy in acute myeloid leukemia. Sci Rep 7:14684
Muller, Laurent; Mitsuhashi, Masato; Simms, Patricia et al. (2016) Tumor-derived exosomes regulate expression of immune function-related genes in human T cell subsets. Sci Rep 6:20254
Pollack, Ian F; Jakacki, Regina I; Butterfield, Lisa H et al. (2016) Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas. Neuro Oncol 18:1157-68
Whiteside, Theresa L (2016) Tumor-Derived Exosomes and Their Role in Tumor-Induced Immune Suppression. Vaccines (Basel) 4:
Yuan, Jianda; Hegde, Priti S; Clynes, Raphael et al. (2016) Novel technologies and emerging biomarkers for personalized cancer immunotherapy. J Immunother Cancer 4:3
Hong, Chang-Sook; Funk, Sonja; Muller, Laurent et al. (2016) Isolation of biologically active and morphologically intact exosomes from plasma of patients with cancer. J Extracell Vesicles 5:29289

Showing the most recent 10 out of 43 publications