title: Effect of pemetrexed on innate immune killer cells and adaptive immune T cells in subjects with adenocarcinoma of the pancreas.
abstract: Baseline levels of innate and adaptive immune cell functions were studied in patients with pancreatic cancer. The effects of pemetrexed were measured at 7 and 14 days after initial therapy then 14 days after combination therapy with gemcitabine. Pretherapy levels of absolute numbers of natural killer (NK) cells positively correlated with survival. Cytolytic units of NK activity correlated positively with NK cell numbers. Pemetrexed decreased NK cytolytic units to significance when combined with gemcitabine. Pemetrexed increased intracellular accumulation of interferon gamma (IFNγ) in NK cells that correlated negatively with survival. Addition of gemcitabine decreased IFNγ-producing NK cells to baseline. Memory (CD45RO*) T cells enumerated at baseline correlated negatively with survival but were decreased by pemetrexed therapy. Memory T cells were increased in subjects with greater B7-H3 expression in tumor tissue, whereas OX40*-activated total T cells and helper T-cell subset were decreased. FoxP3*, CD8* T cells correlated positively with progression-free interval and survival. In conclusion, innate NK-cell immunity and FoxP3*, CD8* T cells seemed beneficial to pancreatic cancer patients. Higher levels of B7-H3 expression in pancreatic tumors were detrimental to effective immunity. Although pemetrexed therapy increased activation of a subset of NK cells to produce IFNγ, addition of gemcitabine abated those responses, decreasing IFNγ-producing NK cells, whereas NK cells producing interleukin-2 without IFNγ at this timepoint positively correlated with survival. Innate immunity and adaptive immunity thus are important in defense against pancreatic cancer. Progression-free interval and survival were longer than observed in a phase III trial where gemcitabine preceded pemetrexed suggesting that a larger trial of pemetrexed preceding gemcitabine is warranted.
authors.affiliation: Division of Oncology, Hematology and Stem Cell Transplantation, Rush University Medical Center, 1725 West Harrison St, Chicago, IL 60612, USA.
authors.forename: Marcherie
authors.initials: M
authors.lastname: Davis
authors.forename: Kevin
authors.initials: K
authors.lastname: Conlon
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Bohac
authors.forename: John
authors.initials: J
authors.lastname: Barcenas
authors.forename: William
authors.initials: W
authors.lastname: Leslie
authors.forename: LaTanja
authors.initials: L
authors.lastname: Watkins
authors.forename: Ihab
authors.initials: I
authors.lastname: Lamzabi
authors.forename: Youping
authors.initials: Y
authors.lastname: Deng
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Janet M D
authors.initials: JM
authors.lastname: Plate
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000230:Adenocarcinoma / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D060887:B7 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005971:Glutamates / Q000008:administration & dosage* / Q000009:adverse effects; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000068437:Pemetrexed; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D000093542:Gemcitabine
chemical_list: D060887:B7 Antigens; C423237:CD276 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005971:Glutamates; D007376:Interleukin-2; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D007371:Interferon-gamma; D000093542:Gemcitabine