Blockade of CCL1 inhibits T regulatory cell suppressive function enhancing tumor immunity without affecting T effector responses.
Intratumoral accumulation of T regulatory cells (Tregs) creates an immunosuppressive environment that reduces the efficacy of antitumor immunotherapy. The immunosuppressive milieu within tumors is largely brought about by the presence of Tregs, which maintain self-tolerance by directly inhibiting T cells, NK cells, and dendritic cells. Depletion of Tregs enhances antitumor immune responses; however, current depletion therapies also affect the function of CD4 and CD8 T effector cells. Previous studies from our laboratory indicate that intratumoral delivery of CpG-ODN strongly reduces the levels of Tregs within the tumor, which is mainly mediated by IL-6. Because IL-6 promotes growth of some human cancers, alternate pathways to inactivate Tregs were sought through microarray analysis, resulting in gene candidates that can be exploited to modulate the function of Tregs. Analysis of these candidates indicates that neutralization of chemokine (C-C motif) ligand 1 (CCL1) prevented de novo conversion and suppressive function of Tregs without affecting the function of T effector cells. The combination of CpG-ODN and anti-CCL1 treatments induced complete rejection of tumors in BALB-neuT tolerant mice, and result in the generation of long-term protective memory responses. Tumor rejection correlated with changes in the lymphocyte composition within the tumor; we observed decreased Treg numbers and a concomitant accumulation of tumoricidal cells such as CD8+NKG2D+ and NK cells. These studies demonstrate that neutralization of CCL1 can be used as an adjuvant to antitumor immunotherapy, as a means of reversing the immunosuppressive function of Tregs without compromising T cell effector function.
Hoelzinger
Dominique B
DB
Department of Immunology, Mayo Clinic College of Medicine, Scottsdale, AZ 85259, USA.
Smith
Shannon E
SE
Mirza
Noweeda
N
Dominguez
Ana Lucia
AL
Manrique
Soraya Zorro
SZ
Lustgarten
Joseph
J
D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D054402:Chemokine CCL1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology*
C408982:CPG-oligonucleotide; D054402:Chemokine CCL1; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides