Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However, chemotherapy-induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast, several chemotherapeutic drugs modulate antitumor immune responses, despite not inducing classic ICD. In addition, in many cases tumor cells do not die after treatment. Here, using docetaxel, one of the most widely used cancer chemotherapeutic agents, as a model, we examined phenotypic and functional consequences of tumor cells that do not die from immunogenic cell death. Docetaxel treatment of tumor cells did not induce ATP or HMGB1 secretion, or cell death. However, calreticulin exposure was observed in all cell lines examined after chemotherapy treatment. Killing by CEA, MUC-1, or PSA-specific CD8+ CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen-processing machinery, and mediated largely by calreticulin membrane translocation, as determined by functional knockdown of calreticulin, PERK, or calreticulin-blocking peptide. A docetaxel-resistant cell line was selected (MDR-1+, CD133+) by continuous exposure to docetaxel. These cells, while resistant to direct cytostatic effects of docetaxel, were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. We provided an operational definition of "immunogenic modulation," where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to immunogenic cell death and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy. Chemotherapy with platinum doublets, including cisplatin plus vinorelbine, is standard of care for non-small cell lung cancer (NSCLC). 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. However, the effects of cisplatin/vinorelbine on tumor sensitivity to T-cell cytotoxicity and its molecular mechanisms have not been fully elucidated. Here, 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 MHC-restricted perforin/granzyme-mediated CTL killing. These studies also demonstrate that exposure to chemotherapy markedly decreased the protein secretion ratio of TGF-beta/IL-8. We examined the gene expression profile of two lung tumor cell lines in order 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 TNF-alpha, IL8, CXCL5, and BCL-2 like genes. 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 pro-apoptotic/anti-apoptotic 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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Donahue, Renee N; Duncan, Brynn B; Fry, Terry J et al. (2014) A pan inhibitor of DASH family enzymes induces immunogenic modulation and sensitizes murine and human carcinoma cells to antigen-specific cytotoxic T lymphocyte killing: implications for combination therapy with cancer vaccines. Vaccine 32:3223-31
Farsaci, Benedetto; Donahue, Renee N; Coplin, Michael A et al. (2014) Immune consequences of decreasing tumor vasculature with antiangiogenic tyrosine kinase inhibitors in combination with therapeutic vaccines. Cancer Immunol Res 2:1090-102
Hodge, James W; Garnett, Charlie T; Farsaci, Benedetto et al. (2013) Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int J Cancer 133:624-36
Higgins, Jack P; Bernstein, Michael B; Hodge, James W (2009) Enhancing immune responses to tumor-associated antigens. Cancer Biol Ther 8:1440-9
Hodge, James W; Higgins, Jack; Schlom, Jeffrey (2009) Harnessing the unique local immunostimulatory properties of modified vaccinia Ankara (MVA) virus to generate superior tumor-specific immune responses and antitumor activity in a diversified prime and boost vaccine regimen. Vaccine 27:4475-82
Madan, Ravi A; Arlen, Philip M; Mohebtash, Mahsa et al. (2009) Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs 18:1001-11
Ferrara, Theresa A; Hodge, James W; Gulley, James L (2009) Combining radiation and immunotherapy for synergistic antitumor therapy. Curr Opin Mol Ther 11:37-42
Garnett, Charlie T; Schlom, Jeffrey; Hodge, James W (2008) Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement. Clin Cancer Res 14:3536-44
Chakraborty, Mala; Gelbard, Alexander; Carrasquillo, Jorge A et al. (2008) Use of radiolabeled monoclonal antibody to enhance vaccine-mediated antitumor effects. Cancer Immunol Immunother 57:1173-83
Wansley, Elizabeth K; Chakraborty, Mala; Hance, Kenneth W et al. (2008) Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses. Clin Cancer Res 14:4316-25

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