We hypothesize that pulmonary macrophages suppress anti-cancer immunity in the lung and play a pathologic role in the aggressive and refractory nature of lung cancer. With the advent of adoptive immunotherapies it is increasingly important to understand how cytotoxic lymphocytes are regulated in the host environment. In preliminary work we demonstrated that alveolar macrophages (AMs) are potent inhibitors of otherwise functional NK and LAK cells. This proposal will quantitate the specificity and extent of this inhibitory phenomenon, its temporal requirements and reversibility, and the subcellular mechanisms which mediate it. Fresh human Ams will be obtained and tested for their ability to inhibit the cytotoxic function of NK cells, LAK cells, antigen-specific cytotoxic T-lymphocytes (CTLs) and antibody-directed cell cytotoxicity (ADCC). By comparing the ability to inhibit these diverse cytotoxic effectors, which have varying mechanisms of target recognition, we will gain insight into the mechanism and specificity of inhibition. We will also examine the capacity of AMs to prevent the induction of an anti-cancer response. The kinetics of inhibition will be determined, as will the potential for reversing inhibition once lymphocytes are removed from the AM environment. IL-2 will be examined for its capacity to restore cytotoxic activity, and GM-CSF, which has been shown to affect the interaction between monocytes and LAK cells, will be tested for its ability to modulate inhibition. Indirect evidence suggests that binding between AMs and LAK cells is central to the inhibitory process. The nature and importance of cell-to-cell binding will be investigated using anti-LFA antibody and temperature modulation. Finally, we have observed inhibitory activity in isolated AM membranes and we will attempt to quantitate and characterize this membrane-associated inhibitory signal. Our ultimate goal is to optimize host immunity and impact on the natural history and treatment of pulmonary neoplasms.
