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1.
Cancer Res ; 78(18): 5340-5348, 2018 09 15.
Article in English | MEDLINE | ID: mdl-30026324

ABSTRACT

CCR8 is a chemokine receptor expressed principally on regulatory T cells (Treg) and is known to be critical for CCR8+ Treg-mediated immunosuppression. Recent studies have demonstrated that CCR8 is uniquely upregulated in human tumor-resident Tregs of patients with breast, colon, and lung cancer when compared with normal tissue-resident Tregs. Therefore, CCR8+ tumor-resident Tregs are rational targets for cancer immunotherapy. Here, we demonstrate that mAb therapy targeting CCR8 significantly suppresses tumor growth and improves long-term survival in colorectal tumor mouse models. This antitumor activity correlated with increased tumor-specific T cells, enhanced infiltration of CD4+ and CD8+ T cells, and a significant decrease in the frequency of tumor-resident CD4+CCR8+ Tregs. Tumor-specific CD8+ T cells displayed lower expression of exhaustion markers as well as increased functionality upon restimulation. Treatment with anti-CCR8 mAb prevented de novo induction and suppressive function of Tregs without affecting CD8+ T cells. Initial studies explored a combinatorial regimen using anti-CCR8 mAb therapy and a Listeria monocytogenes-based immunotherapy. Anti-CCR8 mAb therapy synergized with L. monocytogenes-based immunotherapy to significantly delay growth of established tumors and to prolong survival. Collectively, these findings identify CCR8 as a promising new target for tumor immunotherapy and provide a strong rationale for further development of this approach, either as a monotherapy or in combination with other immunotherapies.Significance: Inhibition of CCR8 represents a promising new cancer immunotherapy strategy that modulates tumor-resident regulatory T cells to enhance antitumor immunity and prolong patient survival. Cancer Res; 78(18); 5340-8. ©2018 AACR.


Subject(s)
Cancer Vaccines/immunology , Colonic Neoplasms/immunology , Colonic Neoplasms/therapy , Receptors, CCR8/antagonists & inhibitors , Animals , Antibodies, Monoclonal/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Humans , Immune Tolerance , Immunosuppression Therapy , Immunotherapy , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Receptors, CCR8/immunology , T-Lymphocytes, Regulatory/immunology , Treatment Outcome , Tumor Microenvironment/immunology , Up-Regulation
2.
J Immunol ; 194(12): 5825-37, 2015 Jun 15.
Article in English | MEDLINE | ID: mdl-25957168

ABSTRACT

Thymic involution and the subsequent amplified release of autoreactive T cells increase the susceptibility toward developing autoimmunity, but whether they induce chronic inflammation with advanced age remains unclear. The presence of chronic low-level proinflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality in virtually every chronic age-related disease. To determine how thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging, we used a Foxn1 conditional knockout mouse model that induces accelerated thymic involution while maintaining a young periphery. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by a chronic inflammatory phenotype consisting of cellular infiltration into non-lymphoid tissues, increased TNF-α production, and elevated serum IL-6. Autoreactive T cell clones were detected in the periphery of Foxn1 conditional knockout mice. A failure of negative selection, facilitated by decreased expression of Aire rather than impaired regulatory T cell generation, led to autoreactive T cell generation. Furthermore, the young environment can reverse age-related regulatory T cell accumulation in naturally aged mice, but not inflammatory infiltration. Taken together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a contributing source of chronic inflammation (inflammaging).


Subject(s)
Autoimmunity , Clonal Selection, Antigen-Mediated , Inflammation/immunology , T-Lymphocyte Subsets/immunology , Thymus Gland/immunology , Age Factors , Animals , Cellular Microenvironment , Chronic Disease , Clonal Deletion/genetics , Clonal Deletion/immunology , Disease Models, Animal , Forkhead Transcription Factors/genetics , Gene Knockdown Techniques , Immunophenotyping , Inflammation/genetics , Inflammation/metabolism , Lymphocyte Activation/immunology , Mice , Mice, Knockout , Phenotype , T-Lymphocyte Subsets/metabolism , Thymocytes/cytology , Thymocytes/immunology , Thymocytes/metabolism
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