Abstract
Concomitant tumor immunity describes immune responses in a host with a progressive tumor that rejects the same tumor at a remote site. In this work, concomitant tumor immunity was investigated in mice bearing poorly immunogenic B16 melanoma. Progression of B16 tumors did not spontaneously elicit concomitant immunity. However, depletion of CD4+ T cells in tumor-bearing mice resulted in CD8+ T cell–mediated rejection of challenge tumors given on day 6. Concomitant immunity was also elicited by treatment with cyclophosphamide or DTA-1 monoclonal antibody against the glucocorticoid-induced tumor necrosis factor receptor. Immunity elicited by B16 melanoma cross-reacted with a distinct syngeneic melanoma, but not with nonmelanoma tumors. Furthermore, CD8+ T cells from mice with concomitant immunity specifically responded to major histocompatibility complex class I–restricted epitopes of two melanocyte differentiation antigens. RAG1 −/− mice adoptively transferred with CD8+ and CD4+ T cells lacking the CD4+CD25+ compartment mounted robust concomitant immunity, which was suppressed by readdition of CD4+CD25+ cells. Naturally occurring CD4+CD25+ T cells efficiently suppressed concomitant immunity mediated by previously activated CD8+ T cells, demonstrating that precursor regulatory T cells in naive hosts give rise to effective suppressors. These results show that regulatory T cells are the major regulators of concomitant tumor immunity against this weakly immunogenic tumor.
Highlights
Concomitant tumor immunity describes the immune response in a host bearing a progressive tumor that rejects an inoculum of the same tumor at a distant site
To determine if concomitant immunity is elicited by a poorly immunogenic tumor, B16 tumors were inoculated in the right flanks of C57BL/6 hosts, and 3, 6, 9, or 12 d later, an identical inoculum was given in the opposite flank
The work of North et al ف20 yr ago carefully characterized the immune response to Meth A fibrosarcoma as an equilibrium between tumor-induced CD8ϩ effector and CD4ϩCD5ϩ suppressor T cells [3, 8]
Summary
Concomitant tumor immunity describes the immune response in a host bearing a progressive tumor that rejects an inoculum of the same tumor at a distant site. The phenomenon was first reported by Ehrlich [1] and Bashford et al [2] in the early 1900’s, these early observations could be attributed to alloantigen recognition and transplantation immunity in outbred mice. The establishment of inbred mouse strains and syngeneic tumor transplants directly established the relevance of concomitant immunity to tumor immunity. More than 70 yr later, North et al conducted a series of notable experiments demonstrating concomitant immunity in BALB/c mice bearing the chemically induced Meth A fibrosarcoma [3,4,5,6,7].
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