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Sensitizing Prostate Cancer Cells to IL‐27 Immunotherapy by Chemotherapy Induced Immunogenic Modulation
Author(s) -
Kumar Shreya,
Figueiredo Marxa
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.494.3
Subject(s) - docetaxel , prostate cancer , medicine , chemotherapy , immunotherapy , cancer research , immune system , cancer , metastasis , prostate , cancer cell , oncology , immunology
Bone‐metastasis occurs in most patients suffering from advanced prostate cancer. Treatment options for such patients are currently limited and immunogenic modulation (IMO) is emerging as a possible therapeutic option. IMO involves changes in cancer cell‐phenotype in response to treatment with sub‐clinical doses of chemotherapy which makes cells more susceptible to an immune attack. By utilizing the immune system to eliminate tumors, one can effectively reduce chemotherapy toxicity and the associated side‐effects. Moreover, an IMO approach may enable one to treat tumors unresponsive or resistant to chemotherapy. Our goal for this project is to characterize and optimize the response of prostate cancer cells to sub‐lethal doses of chemotherapy drugs. We examined gene expression changes in cancer cells in vitro following exposure to varying sub‐lethal concentrations of chemotherapeutics and optimized cellular response with respect to the duration of treatment, drug concentrations, and different cell types by using quantitative Polymerase Chain Reaction (qPCR), viability assays, and flow cytometry approaches. Expression levels of five markers of IMO were investigated in two prostate cancer cell lines. For example, the carcinoembryonic (CEA) gene, which is a tumor antigen and previously associated with IMO, was significantly upregulated in response to sublethal doses of chemotherapy and thus was selected for subsequent characterization. Of the five drugs that we tested across two cell lines, Cabozantinib and Docetaxel showed the most promising response in upregulating CEA. PC3 cells (a human prostate cancer adenocarcinoma cell line) showed a ~15‐fold change in CEA expression 48 h post‐docetaxel treatment. Similarly, Cabozantinib promoted a ~11‐fold CEA upregulation after 72 h of treatment. These gene expression changes were confirmed using flow cytometry. These results suggest that sub‐lethal doses of chemotherapy might induce tumor cell sensitivity to CEA‐specific T‐cell mediated killing. Further studies in in vivo models to profile tumor‐infiltrating immune effectors will help characterize the associated immune response and examine whether chemotherapy and immunotherapy (IL‐27) can act in synergy to enhance the anti‐tumor immune response. We anticipate that such combinational therapy will open new avenues for treating bone‐metastatic prostate cancer while reducing chemotherapy‐associated toxicity. Support or Funding Information NIH NCI R01CA196947 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .