MISSION

IMMUNE FUNCTION IMPACTED BY TOBACCO SMOKE
CURRENT RESEARCH
A2A RECEPTOR ANTAGONISM AS A NOVEL MEANS TO ENHANCE VACCINE THERAPY FOR THE TREATMENT
AND PREVENTION OF BREAST CANCER
Jonathan D. Powell, MD, PhD; Columbia University; CIA 2006
The ability of the immune system to specifically recognize antigen makes it a potentially powerful tool in
terms of developing modalities to treat breast cancer. However, in spite of many recent advances in
identifying tumor antigens, immunotherapy has yet to live up to its full potential. In part this is due to the
ability of tumors to evade immune destruction by turning off tumor-antigen specific immune cells.
Recently, data have emerged demonstrating that the A2a adenosine receptor plays an important role in
downmodulating immune responses. Dr. Powell’s lab has been able to demonstrate that A2a engagement
of T cells not only inhibits T cell function but also promotes the generation of T cell tolerance and T-
regulatory cells. Since the tumor microenvironment contains high concentrations of adenosine, the
investigators propose that tumor-derived adenosine acts to inhibit immune function and promote tumorspecific
T cell tolerance. Indeed, recent data using A2a receptor (A2aR) null mice indicate that such mice
mount more robust antitumor responses leading to their enhanced ability to reject tumor challenge. In
addition, these mice respond better to tumor-specific vaccines as treatment for pre-existing tumors.
Mechanistically, these data suggest that A2aR mice are resistant to anergy induction in vivo and develop
less antigen-specific Lag-3+ regulatory T cells. Currently, the research team is examining the affect of
specific A2aR antagonists to enhance tumor vaccines in tumor-bearing wild-type mice. The PI predicts that
such studies will identify an A2aR antagonist compound that can be integrated into clinical trials.
FAMRI Supported Publications
Sikder HA, Huso DL, Zhang H, Wang B, Ryu B, Hwang ST, Powell JD, Alani RM. Disruption of Id1
reveals major differences in angiogenesis between transplanted and autochthonous tumors. Cancer Cell
2003;4:291-299.
Zarek PE, HuangCT, Lutz ER, Kowalski J, Horton MR,Linden J, Drake CG, Powell JD. Blood
2008;111:251-259.
SECOND HAND TOBACCO SMOKE, IMMUNITY AND ALLOGRAFT REJECTION
Zhenhua Dai, MD, PhD; University of Texas Health Center at Tyler; CIA 2008
Transplantation is emerging as a more common and critical approach to save lives of patients at the endstage
of various organ diseases including the heart and kidney. However, studies on the role of cigarette
smoking in allograft rejection and alloimmunity in a cause-effect manner are lacking.
Current protocols to induce long-term allograft survival include conventional immunosuppression,
costimulatory blockade and the generation of regulatory T cells (Treg), etc. In particular, approaches to
suppress memory T cell generation but induce Treg cells are essential for long-term allograft survival. Dr.
Dai’s preliminary data have shown that SHS increases memory T cell number and hinders allograft survival
induced by CD40/CD154 costimulatory blockade. In this proposal he hypothesizes that SHS shortens
allograft survival by suppressing Treg cell development but promoting memory T cell recall. In Aim 1, the
PI investigates the impact of SHS on the function of memory CD4+ and CD8+ T cells. In Aim 2, he will
study whether SHS suppresses the generation and function of CD4+CD25+FoxP3+ Treg cells. Finally, in
Aim 3, he will examine whether targeting memory T cells and administering Treg cells suppress allograft
rejection related to SHS. In this study, a murine cardiac transplant model will be implemented and
recipient mice will be exposed to a precision-guided smoke chamber mimicking SHS. This study for the
first time will provide insight into the immunologic mechanisms by which SHS promotes allograft
rejection. This proposal also has clinical implications for the prevention and treatment of graft rejection
caused by the exposure to SHS.
ALTERATIONS IN DENDRITIC CELL-MEDIATED IMMUNITY CAUSED BY SMOKING
Robert Vassallo, MD; Mayo Clinic; YCSA 2005
Dr. Vassallo proposes that cigarette smoking and nicotine suppress the function of dendritic cells in a
very specific fashion. The PI hypothesizes that smoking diminishes host immune responses necessary for
elimination of tumors and infections, and enhances the development of immune responses that lead to
allergy and asthma. Using a murine smoking model the goals are to: 1) determine the effect of smoking on
P A G E 1 9 1