Regulatory T Cells in Tumor-Associated Tertiary Lymphoid Structures Suppress Anti-tumor T Cell Responses

• Published in: Immunity (Cambridge, Mass.) Vol. 43; no. 3; pp. 579 - 590
• Main Authors: Joshi, Nikhil S., Akama-Garren, Elliot H., Lu, Yisi, Lee, Da-Yae, Chang, Gregory P., Li, Amy, DuPage, Michel, Tammela, Tuomas, Kerper, Natanya R., Farago, Anna F., Robbins, Rebecca, Crowley, Denise M., Bronson, Roderick T., Jacks, Tyler
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.09.2015; Elsevier Limited
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - immunology; Adenocarcinoma - metabolism; Animals; Cell Proliferation; Cells, Cultured; Dendritic Cells - immunology; Dendritic Cells - metabolism; Flow Cytometry; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Immune system; Immunohistochemistry; Immunotherapy; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lymphocyte Activation - immunology; Lymphocyte Depletion; Lymphocytes; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Medical research; Mice, Transgenic; Microscopy, Confocal; Mortality; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Rodents; Scholarships & fellowships; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tumors
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2015.08.006

Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically engineered mouse model of lung adenocarcinoma and found that Treg cells suppressed anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs have been described in human lung cancers, but their function remains to be determined. TLSs in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen-presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLSs upon Treg cell depletion, leading to tumor destruction. Thus, we propose that Treg cells in TA-TLSs can inhibit endogenous immune responses against tumors, and targeting these cells might provide therapeutic benefit for cancer patients. [Display omitted] •TA-TLSs form adjacent to advanced lung tumors•TA-TLSs have features and functions of lymph nodes•Treg cells in TA-TLSs actively suppress immune responses•Therapeutic Treg cell depletion causes immune-mediated tumor destruction Intratumoral regulatory T (Treg) cells are important in lung cancer, but it has been difficult to dissect their mechanisms of action. Jacks and colleagues demonstrate that intratumoral Treg cells function within tumor-associated tertiary lymphoid structures to suppress anti-tumor T cell responses in a mouse model of lung cancer.