Defining the Molecular Signature of Chemotherapy-Mediated Lung Tumor Phenotype Modulation and Increased Susceptibility to T-Cell Killing

Abstract

Chemotherapy with platinum doublets, including cisplatin plus vinorelbine, is standard of care for non-small-cell lung cancer. Sublethal exposure to certain chemotherapeutic agents has been demonstrated to alter the phenotype or biology of human tumor cells, rendering them more susceptible to cytotoxic T lymphocyte (CTL)-mediated lysis. The effects of cisplatin/vinorelbine on tumor sensitivity to T-cell cytotoxicity and its molecular mechanisms, however, have not been fully elucidated. We examined the effect of this chemotherapy on growth, cell-surface phenotype, and CTL-mediated lysis of five distinct human lung carcinoma cell lines in vitro and examined the molecular mechanisms associated with enhanced CTL sensitivity. These studies demonstrate that sublethal exposure of human lung tumor cells to the platinum doublet modulates tumor cell phenotype and increases sensitivity to major histocompatibility complex-restricted perforin/granzyme-mediated CTL killing. These studies also demonstrate that exposure to chemotherapy markedly decreased the protein secretion ratio of transforming growth factor-β/interleukin (IL)-8. We examined the gene expression profile of two lung tumor cell lines to identify a shared gene signature in response to sublethal cisplatin/vinorelbine and found coordinate expression of only 16 transcripts, including those for cytokine/chemokine expression and apoptosis such as tumor necrosis factor-α, IL8, CXCL5, and B cell lymphoma-2-like genes (BCL-2). Overall, these results suggest that sublethal exposure to cisplatin/vinorelbine increases sensitivity to perforin/granzyme-mediated CTL killing by modulation of (a) tumor phenotype, (b) cytokine/chemokine milieu, and (c) the proapoptotic/antiapoptotic gene ratio. The data presented here propose a complex mechanism that is distinct from and complementary to that of immunogenic cell death. This molecular signature may be useful in predicting responses to immunotherapy as well as provide the rationale for the potential clinical benefit of the combined use of vaccine with cisplatin/vinorelbine regimens.