PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer.
Negative costimulation on T cells is exploited by both prostate cancer and melanoma to evade antitumor immunity. Blocking such mechanisms restores antitumor immunity as was demonstrated by the improved survival of patients with metastatic melanoma after treatment with an antibody blocking the CTLA-4 inhibitory receptor (ipilimumab). Enhanced expression of another inhibitory immunoreceptor, programmed death-1 (PD-1), and its ligand, PD-L1, was found to correlate with a poor prognosis in prostate cancer and melanoma. PD-1-blocking antibodies are being developed to modulate antitumor immune responses. To support preclinical and clinical development of anti-PD-1 therapy, we sought to develop biomarker assays that can detect the effect of PD-1-blocking agents in whole blood and peripheral blood mononuclear cells. In this study, we assessed the effect of PD-1 blockade in modulating super antigen (staphylococcus enterotoxin B)-induced and recall antigen (tetanus toxoid)-induced T-cell reactivity in vitro using whole blood and peripheral blood mononuclear cells from patients with advanced melanoma, prostate cancer, and healthy controls. PD-1 blockade was found to shift antigen-induced cellular reactivity toward a proinflammatory Th1/Th17 response, as evidenced by enhanced production of interferon γ, interleukin (IL)-2, tumor necrosis factor α, IL-6, and IL-17 and reduced production of the Th2 cytokines IL-5 and IL-13. It is interesting to note that suppression of Th2 responsivity was seen with whole blood cells only from patients with cancer. Taken together, we identified novel biomarker assays that might be used to determine the functional consequences of PD-1 blockade in peripheral blood cells from patients with cancer. How these assays translate to the local antitumor response remains to be established in a clinical setting.
Department of Immune Therapeutics, Merck Research Laboratories, MSD, Oss, The Netherlands. j.dulos@live.com
John
J
Dulos
Gregory J
GJ
Carven
Susan J
SJ
van Boxtel
Sabine
S
Evers
Lilian J A
LJ
Driessen-Engels
Willemijn
W
Hobo
Monika A
MA
Gorecka
Anton F J
AF
de Haan
Peter
P
Mulders
Cornelis J A
CJ
Punt
Joannes F M
JF
Jacobs
Jack A
JA
Schalken
Egbert
E
Oosterwijk
Hans
H
van Eenennaam
Annemieke M
AM
Boots
D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000097:blood / Q000276:immunology*; D002469:Cell Separation; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008545:Melanoma / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology
D019138:Antibodies, Blocking; D014408:Biomarkers, Tumor; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor