Prenatal Exposure to Cigarette Smoke Alters Later-Life Antitumor Cytotoxic T-Lymphocyte (CTL) Activity Via Possible Changes in T-Regulatory Cells

Abstract

Epidemiological studies suggest that maternal smoking increases the incidence in the progeny of certain childhood cancers. Our previous study in mice demonstrated the feasibility of such an association by demonstrating that prenatal exposure to cigarette smoke (CS) elevated the incidence of transplanted tumors and reduced cytotoxic T-lymphocyte (CTL) activity in juvenile male offspring. The current study extends these findings by investigating the relationship between CS-induced CTL suppression and effects on regulators of effector T-cell activity, such as T-regulatory (T_reg; CD4⁺CD25⁺Foxp3⁺) cells and transforming growth factor (TGF)-β. Results here demonstrate that in utero exposure to CS, at a maternal particle concentration of 15 mg/m³ (4 h/d, 5 d/wk), significantly reduced ex vivo CTL activity of whole splenocytes (and isolated CD8⁺ cells) against tumor cells both before and after injection of prenatally exposed mice with EL4 lymphoma cells. In contrast, prenatal CS exposure significantly increased levels of thymic T_reg cells in a time-dependent manner following tumor cell injection. In vitro production of TGF-β by splenocytes recovered from prenatally exposed, tumor-bearing mice was also altered. Neither prenatal CS exposure nor subsequent administration of EL4 cells exerted any marked effects on lymphoid organ weights, cellularity, or histologic profiles. Given that T_reg cells and TGF-β suppress effector T-cell activities, these findings suggest possible immune mechanisms by which early exposure to CS reduces CTL tumoricidal activity during tumor cell development. Data suggest that children of smoking mothers may be less able to mount an appropriate adaptive immune response to tumors, thus increasing their risk for some cancers later in life.

Acknowledgments

This work was supported by a Novartis Graduate Fellowship and (in part) by an NYU NIEHS Center Grant (ES00260). The flow cytometry facility at SUNY Upstate Medical University was developed with resources from the NIH and a New York State “Star” grant. The authors thank Shannon Doherty-Lyons and Maureen Sisco for their technical assistance, and Dr. Jack R. Harkema (MSU) for the histolopathology and cytokine analyses.