Evidence for oligoclonal T-cell response in a metastasis of renal cell carcinoma responding to vaccination with autologous tumor cells and transfer of in vitro-sensitized vaccine-draining lymph node lymphocytes.
Peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) of a patient with von Hippel-Lindau disease and renal cell carcinoma were studied for the T-cell receptor beta chain variable region (TCR-V beta) repertoire. The patient was vaccinated with irradiated autologous tumor cells from a renal tumor mass, a vaccine-draining lymph node was removed, and lymphocytes were cultured in the presence of autologous tumor cells and low-dose interleukin 2 (IL2). These lymphocytes were adoptively transferred to the patient together with systemic IL2 (30,000 IU/kg every 8 h). Analysis of TCR-V beta expression was performed by polymerase chain reaction in PBL before, during, and after therapy, in vaccine-draining lymph node lymphocytes, and in TIL obtained from moderately infiltrated, nonresponding renal tumor mass and from a more intensely infiltrated lung metastasis, which was responding to treatment. Significant differences in the expression of TCR-V beta 13.1 by T-cells recovered from these various sites were observed. Also, TIL recovered from the responding lung metastasis and cultured in the presence of IL2 gave rise to autologous tumor-reactive CD4+ T-cells, whereas the nonresponsive renal tumor yielded a mixture of T- and natural killer cells. In PBL obtained prior to treatment and during IL2 therapy, expression of V beta 13.1 was 0.7 and 1.8%, respectively, of the total V beta gene repertoire. Fresh vaccine-draining lymph node lymphocytes contained 5.9% of V beta 13.1-expressing T-cells. After IL2 therapy, V beta 13.1 gene expression increased to 5.4% in PBL. In the nonresponding tumor mass, the frequency of V beta 13.1 gene expression among TIL was 12%, whereas in the responding, highly infiltrated nodule, it was 28%, with a striking loss of expression of other V beta gene families. Sequencing of the amplified product of V beta 13.1 complementary DNA from the responding pulmonary metastasis showed restrictions in the complementarity-determining region 3. Thus, in vivo expansion of V beta 13.1-expressing CD4+ T-cells, possibly in response to a tumor-associated antigen, occurred in the responding tumor mass following this form of therapy and correlated with tumor course.
Weidmann
E
E
Department of Pathology, University of Pittsburgh, Pennsylvania 15213.
Logan
T F
TF
Yasumura
S
S
Kirkwood
J M
JM
Trucco
M
M
Whiteside
T L
TL
D000595:Amino Acid Sequence; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D016219:Immunotherapy, Adoptive; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction / Q000379:methods; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D006623:von Hippel-Lindau Disease / Q000150:complications / Q000276:immunology / Q000473:pathology
D004273:DNA, Neoplasm; D016693:Receptors, Antigen, T-Cell, alpha-beta