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Boosting the immune response against lung cancer

Institution: University of California, Los Angeles
Investigator(s): Marina Stolina, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7FT-0035 Award: $70,000
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Epidemiological studies show a strong correlation between tobacco smoking and lung cancer. It has been documented that the overwhelming majority of lung cancers, greater than 90 % are caused by cigarette smoking. Lung cancer is the leading cause of cancer deaths in the United States and more than 150,000 Americans died from lung cancer in 1997. There are currently fifty million smokers in the U.S. and another fifty million ex-smokers. This means that approximately one third of the U.S. population is at high risk for this terrible disease. With the existing therapeutic efforts, patients with lung cancer have a poor prognosis. Less than 15 % of lung cancer patients live 5 years. Failure of conventional treatments has led to an intensive search for alternative forms of treatment. Successful treatment that relies on the bodies immune system might be achieved through a better understanding of how lung cancer cells escape detection by the immune system (immunosuppression). In our preliminary studies we have found that the immune suppressive action in lung cancer is due to the over-expression of the enzyme cyclooxygenase-2. Cyclooxygenase-2 activity is significantly increased in cancerous tissues compared to their normal counterparts in several different cancer types and our studies are the first to also document this over-expression in human lung cancer. Our preliminary studies indicate that cyclooxygenase-2 expression in lung cancer leads to a decrease in anti tumor immunity. Although the break down products of cyclooxygenase -2 have been identified as suppressing immunity, it is not well understood how this occurs. A basic understanding of the mechanism involved in the immunosuppression caused by the lung tumor will enable us to devise better treatment strategies to control lung cancer.

Final Report
Cyclooxygenase 2 (COX-2), the enzyme at the rate-limiting step of prostanoid production, has been found to be overexpressed in human lung cancer. To evaluate lung tumor COX-2 modulation of antitumor immunity, we studied the antitumor effect of specific genetic or phannacological inhibition of COX-2 in a murine Lewis lung carcinoma (3LL) model. Inhibition of COX-21ed to marked lymphocytec infiltration of the tumor and reduced tumor growth. Treatment of mice with anti-prostaglandin E2 (anti-PGE2) mAb replicated the growth reduction seen in tumor-bearing mice treated with COX-2 inhibitors. COX-2 inhibition was accompanied by a significant decrement in IL-10 and a concomitant restoration of IL-12 production by antigen presenting cells. Because the COX-2 metabolite PGE2 is a potent inducer of IL-10, it was hypothesized that COX-2 inhibition led to antitumor responses by down-regulating production of this potent immunosuppressive cytokine. In support of this concept, transfer of IL-10 transgenic T lymphocytes that overexpress IL 10 under control of the IL-2 promoter, reversed the COX-2 inhibitor-induced antitumor response. We conclude that abrogation of COX-2 expression promotes antitumor reactivity by restoring the balance of interleukins 10 and 12 in vivo.
Publications

Transfer of IL-10 overproducing lymphocytes reverses the antitumor effects of cyclooxygenase 2 inhibition
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Stolina M, Sharma S, Lin Y, et al ABS
Yr: 1999 Vol: 40 Nbr: Abs: Pg: 77

Mechanisms of IL-10 mediated suppression of antigen presentation in lung cancer
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Sharma S, Stolina M, Lin Y, Zhu L, Miller PW, Dubinett SM ABS
Yr: 1999 Vol: 40 Nbr: Abs: Pg: 512

Specific inhibition of cyclooxygenase 2 restores antitumor immunity by altering the balance of IL-10 and IL-12 synthesis
Periodical: Journal of Immunology Index Medicus:
Authors: Stolina M, Sharma S, Lin U ART
Yr: 2000 Vol: 164 Nbr: Abs: Pg: 361-370

Lung cancer cyclooxygenase-2 dependent inhibition of dendritic cells maturation and function
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Stolina M, Sharma S, Zhu L, Dubinett SM ABS
Yr: 2000 Vol: 41 Nbr: 619 Abs: Pg:

Cyclooxygenase-2 dependent invasion and apoptosis resistance in non-small cell lung cancer (NSCLC)
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Dohadwala M, Lou J, Lin Y, et al ABS
Yr: 2000 Vol: 161 Nbr: 3 Abs: A677 Pg: