Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells.
Paraneoplastic neurologic disorders (PNDs) offer an uncommon opportunity to study human tumor immunity and autoimmunity. In small cell lung cancer (SCLC), expression of the HuD neuronal antigen is thought to lead to immune recognition, suppression of tumor growth, and, in a subset of patients, triggering of the Hu paraneoplastic neurologic syndrome. Antigen-specific CTLs believed to contribute to disease pathophysiology were described 10 years ago in paraneoplastic cerebellar degeneration. Despite parallel efforts, similar cells have not been defined in Hu patients. Here, we have identified HuD-specific T cells in Hu patients and provided an explanation for why their detection has been elusive. Different Hu patients harbored 1 of 2 kinds of HuD-specific CD8+ T cells: classical IFN-gamma-producing CTLs or unusual T cells that produced type 2 cytokines, most prominently IL-13 and IL-5, and lacked cytolytic activity. Further, we found evidence that SCLC tumor cells produced type 2 cytokines and that these cytokines trigger naive CD8+ T cells to adopt the atypical type 2 phenotype. These observations demonstrate the presence of an unusual noncytotoxic CD8+ T cell in patients with the Hu paraneoplastic syndrome and suggest that SCLC may evade tumor immune surveillance by skewing tumor antigen-specific T cells to this unusual noncytolytic phenotype.
Roberts
Wendy K
WK
Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021, USA.
Deluca
Ilana J
IJ
Thomas
Ashby
A
Fak
John
J
Williams
Travis
T
Buckley
Noreen
N
Dousmanis
Athanasios G
AG
Posner
Jerome B
JB
Darnell
Robert B
RB
D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D051959:ELAV Proteins / Q000276:immunology*; D000067779:ELAV-Like Protein 4; D000939:Epitopes; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020362:Paraneoplastic Cerebellar Degeneration / Q000276:immunology*
D051959:ELAV Proteins; D000067779:ELAV-Like Protein 4; C498010:ELAVL4 protein, human; D000939:Epitopes; D018793:Interleukin-13; D007371:Interferon-gamma