Impaired interferon signaling is a common immune defect in human cancer.
Immune dysfunction develops in patients with many cancer types and may contribute to tumor progression and failure of immunotherapy. Mechanisms underlying cancer-associated immune dysfunction are not fully understood. Efficient IFN signaling is critical to lymphocyte function; animals rendered deficient in IFN signaling develop cancer at higher rates. We hypothesized that altered IFN signaling may be a key mechanism of immune dysfunction common to cancer. To address this, we assessed the functional responses to IFN in peripheral blood lymphocytes from patients with 3 major cancers: breast cancer, melanoma, and gastrointestinal cancer. Type-I IFN (IFN-alpha)-induced signaling was reduced in T cells and B cells from all 3 cancer-patient groups compared to healthy controls. Type-II IFN (IFN-gamma)-induced signaling was reduced in B cells from all 3 cancer patient groups, but not in T cells or natural killer cells. Impaired-IFN signaling was equally evident in stage II, III, and IV breast cancer patients, and downstream functional defects in T cell activation were identified. Taken together, these findings indicate that defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction.
Critchley-Thorne
Rebecca J
RJ
Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Simons
Diana L
DL
Yan
Ning
N
Miyahira
Andrea K
AK
Dirbas
Frederick M
FM
Johnson
Denise L
DL
Swetter
Susan M
SM
Carlson
Robert W
RW
Fisher
George A
GA
Koong
Albert
A
Holmes
Susan
S
Lee
Peter P
PP
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology*; D015331:Cohort Studies; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007156:Immunologic Memory; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology*; D008875:Middle Aged; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
D000970:Antineoplastic Agents; D016898:Interferon-alpha; D007371:Interferon-gamma