Melanoma-Specific Memory T Cells Are Functionally Active inRetTransgenic Mice without Macroscopic Tumors

Abstract

We previously reported that bone marrows of breast cancer patients contained tumor antigen-specific CD8 + T cells with central or effector memory phenotype. Using a recently developed ret transgenic mouse melanoma model, we now show that bone marrows and tumors of transgenic mice contain high frequencies of CD8 + T cells specific for the melanoma antigen tyrosinase-related protein 2 and showing mostly effector memory phenotype. Moreover, increased numbers of bone marrow tyrosinase-related protein-2-specific effector memory CD8 + T cells are also detected in transgenic animals older than 20 weeks with disseminated melanoma cells in the bone marrow and lymph nodes but showing no visible skin tumors and no further melanoma progression. After a short-term coincubation with dendritic cells generated from the bone marrow and pulsed with melanoma lysates, bone marrow memory T cells from mice without macroscopic melanomas produced IFN-; in vitro and exerted antitumor activity in vivo after adoptive transfer into melanoma-bearing mice. Our data indicate that functionally active bone marrowderived melanoma-specific memory T cells are detectable at the phase of microscopic tumor load, suggesting that thereby they could control disseminated melanoma cells. [Cancer Res 2008;68(22):9451-8]

Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model

“…To address the role of chronic inflammatory mediators in tumor progression in more clinically relevant conditions, we used the ret transgenic mouse model of spontaneous skin melanoma, which resembles human melanoma with respect to clinical development ensuring natural tumor-stroma interactions (27,28). We found an association between increased concentrations of IL-1β and GM-CSF in melanoma lesions and accelerated melanoma progression.…”

“…However, the disease development and the tumorstroma interactions in transplantation tumor models are not comparable with clinical conditions. In contrast, the ret transgenic mouse melanoma model closely resembles human disease as to tumor genetics, histopathology, and clinical development (27,28). Mice expressing the human ret transgene in melanocytes develop spontaneously malignant skin melanoma with metastases in lymph nodes (LNs), lungs, liver, and brain (27,28), similar to the metastatic pattern observed in melanoma in humans (29).…”

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

“…Using ret transgenic mouse model of spontaneous melanoma that mimics human melanoma with respect to tumor growth, metastatic profile, histopathology and expression of melanoma associated antigens [88][89][90], we have studied the frequencies and activities of Gr1 + CD11b + MDSCs in melanoma lesions [48]. It has been found a remarkable accumulation of MDSCs in skin tumors and metastatic lymph nodes that significantly correlated with the tumor progression.…”

mRNA-based dendritic cell immunization improves survival in ret transgenic mouse melanoma model

“…20 In this study, we utilize this chimeric mRNA construct system to examine whether DCs immunization will affect melanoma progression in a spontaneous ret transgenic mouse melanoma model that closely resembles human melanoma regarding histopathology and clinical development. 21,22 In addition, primary skin melanomas and metastases in lymph nodes (LNs) and distant organs of transgenic mice express similar MAAs to those expressed in human melanoma and B16 tumors (such as gp100, Tyr, TRP-1 and TRP-2). 22,23 Our data suggest that immunotherapy with DCs-based antitumor vaccine can significantly improve the survival of tumorbearing ret transgenic mice.…”

“…21,22 In addition, primary skin melanomas and metastases in lymph nodes (LNs) and distant organs of transgenic mice express similar MAAs to those expressed in human melanoma and B16 tumors (such as gp100, Tyr, TRP-1 and TRP-2). 22,23 Our data suggest that immunotherapy with DCs-based antitumor vaccine can significantly improve the survival of tumorbearing ret transgenic mice. Analyzing the mechanism of such effect, we observed elevated frequencies of central and effector memory T-cell subsets in vaccinated mice.…”