Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma.
Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and immune control of metastatic outgrowth. Tumor cells were found to disseminate throughout the body early in development of the primary tumor, even before it became clinically detectable. The disseminated tumor cells remained dormant for varying periods of time depending on the tissue, resulting in staggered metastatic outgrowth. Dormancy in the lung was associated with reduced proliferation of the disseminated tumor cells relative to the primary tumor. This was mediated, at least in part, by cytostatic CD8+ T cells, since depletion of these cells resulted in faster outgrowth of visceral metastases. Our findings predict that immune responses favoring dormancy of disseminated tumor cells, which we propose to be the seed of subsequent macroscopic metastases, are essential for prolonging the survival of early stage cancer patients and suggest that therapeutic strategies designed to reinforce such immune responses may produce marked benefits in these patients.
Eyles
Jo
J
Singapore Immunology Network, BMSI, A-STAR, Singapore.
Puaux
Anne-Laure
AL
Wang
Xiaojie
X
Toh
Benjamin
B
Prakash
Celine
C
Hong
Michelle
M
Tan
Tze Guan
TG
Zheng
Lin
L
Ong
Lai Chun
LC
Jin
Yi
Y
Kato
Masashi
M
Prévost-Blondel
Armelle
A
Chow
Pierce
P
Yang
Henry
H
Abastado
Jean-Pierre
JP
D000818:Animals; D022082:Cellular Structures / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D015166:Monitoring, Immunologic; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology