Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells.

Abstract

The immune response to the tumor can be enhanced by targeting costimulatory molecules on T cells. As the CD70-CD27 costimulatory axis plays an important role in the activation, survival, and differentiation of lymphocytes, we have examined the efficacy of agonistic anti-CD27 antibodies as monotherapies for established melanoma in a murine model. We show that this approach leads to a substantial reduction in the outgrowth of both experimental lung metastases and subcutaneous tumors. Anti-CD27 treatment supports the maintenance of tumor-specific CD8(+) T cells within the tumor, reduces the frequency of FoxP3-expressing CD4(+) T cells within tumors, and potentiates the ability of NK1.1(+) and CD8(+) tumor infiltrating cells to secrete IFNγ upon coculture with tumor cells. The enhanced effector function correlated with lower levels of PD-1 expression on CD8(+) T cells from anti-CD27-treated mice. Despite the modulating effect of anti-CD27 on multiple cell types, only CD8(+) T cells were absolutely required for tumor control. The CD4(+) T cells were dispensable, whereas NK1.1(+) cells were needed during early stages of tumor growth but not for the effectiveness of anti-CD27. Thus, CD27-mediated costimulation provides a potent boost to multiple aspects of the endogenous responses to tumor, and may be exploited to enhance tumor immunity.

• Authors: Drew J Roberts, Nathan A Franklin, Lara M Kingeter, Hideo Yagita, Alison L Tutt, Martin J Glennie, Timothy N J Bullock
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) Vol. 33 Issue 8 Pg. 769-79 (Oct 2010) ISSN: 1537-4513 [Electronic] United States
• PMID: 20842060 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• Antigens, Surface
• Apoptosis Regulatory Proteins
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Tumor Necrosis Factor Receptor Superfamily, Member 7

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, pharmacology)
• Antigens, Surface (genetics, immunology, metabolism)
• Apoptosis Regulatory Proteins (genetics, immunology, metabolism)
• CD4-Positive T-Lymphocytes (drug effects, immunology, metabolism, pathology)
• CD8-Positive T-Lymphocytes (drug effects, immunology, metabolism, pathology)
• Cell Growth Processes (drug effects)
• Cells, Cultured
• Forkhead Transcription Factors (biosynthesis)
• Immunotherapy
• Killer Cells, Natural (drug effects, immunology, metabolism, pathology)
• Lung Neoplasms (immunology, secondary, therapy)
• Lymphocyte Activation (drug effects)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, metabolism, pathology)
• Melanoma, Experimental (immunology, secondary, therapy)
• Mice
• Mice, Inbred C57BL
• Programmed Cell Death 1 Receptor
• Skin Neoplasms (immunology, pathology, therapy)
• Tumor Burden (drug effects)
• Tumor Necrosis Factor Receptor Superfamily, Member 7 (agonists, genetics, immunology)