title: Restoration of expression of signal-transduction molecules in lymphocytes from patients with metastatic renal cell cancer after combination immunotherapy.
abstract: A decrease in lymphocyte signal-transduction molecules, described in cancer patients and patients with chronic infectious diseases, has been proposed as a possible mechanism leading to an impaired immune response in cancer patients. Here we report the effects of combination immunotherapy on the levels of T cell receptor zeta chain and p56lck tyrosine kinase in a retrospective study of cryopreserved lymphocytes from 26 metastatic renal cell carcinoma patients treated with high-dose interleukin-2 (IL-2), interferon alpha (IFNalpha) and ex vivo IL-2-activated lymphocytes. Of the 26 patients, 12 were responders (5 complete and 7 partial) and 14 were non-responders (6 stable and 8 with progressive disease). Prior to treatment, 21 of 26 patients (81%) and 13 of 21 patients (62%) respectively expressed zeta chain and p56lck at less than 50% of the levels observed in healthy controls. During therapy, this low zeta chain and p56lck expression increased to at least 50% of normal in 13 of the 21 patients (62%) and in 6 of the 13 patients (46%) respectively; in the remaining patients expression levels remained at 50% of normal or more, or declined. Although, in this limited study, pretreatment levels of and p56lck did not show significant correlation with antitumor response, 4 of 5 patients that achieved a complete response (80%) corrected both zeta chain and p56lck levels to at least 50% of normal, while restoration of both signal-transduction molecules to such levels was only observed in 3 of 7 partial responders (43%), 1 of 5 patients with stable disease (20%) and 2 of 7 patients with progressive disease (29%). Thus, these results suggest that analysis of changes in signal-transduction molecules may a be useful tool for immunological monitoring of patients throughout immunotherapy, and could provide important information for designing new clinical trials that restore impaired signal transduction while activating T cell responses.
authors.affiliation: Department of Medical and Tumor Immunology, University Hospital Rotterdam - Daniel den Hoed Cancer Center, The Netherlands. gratama@immh.azr.nl
authors.forename: J W
authors.initials: JW
authors.lastname: Gratama
authors.forename: A H
authors.initials: AH
authors.lastname: Zea
authors.forename: R L
authors.initials: RL
authors.lastname: Bolhuis
authors.forename: A C
authors.initials: AC
authors.lastname: Ochoa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000276:immunology / Q000378:metabolism; D016130:Immunophenotyping; D007167:Immunotherapy; D016898:Interferon-alpha / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D020014:K562 Cells; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology* / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D007142:Immunoglobulin gamma-Chains; D016898:Interferon-alpha; D007376:Interleukin-2; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)