Cellular and cytokine-dependent immunosuppressive mechanisms of grm1-transgenic murine melanoma.
Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, and low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increase in the number of activated CD4(+) and CD8(+) lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4(+) T cells, which could constitute both T helper as well as immunosuppressive regulatory T cells, but not CD8(+) T cells, expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response even when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines TGF-β1 and IL-10 became more evident with increased tumor burden. Notably, TGF-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas IL-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of IL-10. Thus, similar to the situation in melanoma patients, both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immunosuppressed state of tumor-bearing grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immunomodulatory therapeutics.
Department of Dermatology, University Hospital of Würzburg, Würzburg, Germany. miriam.alb@gmx.de
Miriam
M
Alb
Christopher
C
Sie
Christian
C
Adam
Suzie
S
Chen
Jürgen C
JC
Becker
David
D
Schrama
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000276:immunology* / Q000378:metabolism*; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008934:Mitogens / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism
D007166:Immunosuppressive Agents; D008934:Mitogens; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; D053773:Transforming Growth Factor beta1; C104077:metabotropic glutamate receptor type 1; D016753:Interleukin-10