Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade.
OBJECTIVE
CTL-associated antigen 4 (CTLA4)-blocking monoclonal antibodies induce long-term regression of metastatic melanoma in some patients, but the exact mechanism is unknown. In this study, biopsies of selected accessible tumor lesions from patients treated with tremelimumab were examined to further elucidate the mechanism of its antitumor activity.


METHODS
Fifteen tumor biopsies from 7 patients who had been treated with tremelimumab (CP-675,206) were collected. Samples were analyzed for melanoma markers, immune cell subset markers, the presence of the T regulatory-specific transcription factor FoxP3 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO).


RESULTS
Clinically responding lesions had diffuse intratumoral infiltrates of CD8(+) T cells that were markedly increased in cases where comparison with a baseline biopsy was available. Nonregressing lesions had sparse, patchy CD8(+) intratumoral infiltrates. Patients with regressing lesions had an increased frequency of CD8(+) cells with or without a concomitant increase in CD4(+) cells. Two of 3 responding patients with paired samples showed a slight increase in the number of FoxP3(+) cells in the postdosing biopsies. In patients with regressing lesions who had paired samples, the intensity of IDO staining in macrophages and/or melanoma cells showed no clear pattern of change postdosing.


CONCLUSIONS
Administration of tremelimumab was associated with massive intratumoral infiltrates of CD8(+) CTLs in patients with regressing tumors but had varying effects on intratumoral infiltrates of CD4(+) and FoxP3(+) cells or intratumoral expression of IDO.
Ribas
Antoni
A
Division of Hematology/Oncology, Department of Medicine, University of California-Los Angeles, Los Angeles, California 90095-1782, USA. aribas@mednet.ucla.edu
Comin-Anduix
Begoña
B
Economou
James S
JS
Donahue
Timothy R
TR
de la Rocha
Pilar
P
Morris
Lilah F
LF
Jalil
Jason
J
Dissette
Vivian B
VB
Shintaku
Itsushi Peter
IP
Glaspy
John A
JA
Gomez-Navarro
Jesus
J
Cochran
Alistair J
AJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology*; D001706:Biopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C520704:tremelimumab