CTLA-4⁺ Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis.

Abstract

The EGFR-targeted antibody cetuximab is effective against head and neck cancer (HNSCC), but in only 15% to 20% of patients, and the variability and extent of cetuximab-mediated cellular immunity is not fully understood. We hypothesized that regulatory T cells (Treg) may exert a functional and clinical impact on antitumor immunity in cetuximab-treated individuals. The frequency, immunosuppressive phenotype, and activation status of Treg and natural killer (NK) cells were analyzed in the circulation and tumor microenvironment of cetuximab-treated patients with HNSCC enrolled in a novel neoadjuvant, single-agent cetuximab clinical trial. Notably, cetuximab treatment increased the frequency of CD4(+)FOXP3(+) intratumoral Treg expressing CTLA-4, CD39, and TGFβ. These Treg suppressed cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and their presence correlated with poor clinical outcome in two prospective clinical trial cohorts. Cetuximab expanded CTLA-4(+)FOXP3(+) Treg in vitro, in part, by inducing dendritic cell maturation, in combination with TGFβ and T-cell receptor triggering. Importantly, cetuximab-activated NK cells selectively eliminated intratumoral Treg but preserved effector T cells. In ex vivo assays, ipilimumab targeted CTLA-4(+) Treg and restored cytolytic functions of NK cells mediating ADCC. Taken together, our results argue that differences in Treg-mediated suppression contribute to the clinical response to cetuximab treatment, suggesting its improvement by adding ipilimumab or other strategies of Treg ablation to promote antitumor immunity.

• Authors: Hyun-Bae Jie, Patrick J Schuler, Steve C Lee, Raghvendra M Srivastava, Athanassios Argiris, Soldano Ferrone, Theresa L Whiteside, Robert L Ferris
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 11 Pg. 2200-10 (Jun 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25832655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antigens, CD
• CTLA-4 Antigen
• CTLA4 protein, human
• FOXP3 protein, human
• Forkhead Transcription Factors
• Transforming Growth Factor beta
• Apyrase
• CD39 antigen
• Cetuximab

Topics

• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antigens, CD (biosynthesis)
• Apyrase (biosynthesis)
• CTLA-4 Antigen (biosynthesis, genetics, immunology)
• Cetuximab
• Clinical Trials, Phase II as Topic
• Cytotoxicity, Immunologic (genetics)
• Female
• Forkhead Transcription Factors (biosynthesis)
• Gene Expression Regulation, Neoplastic (drug effects)
• Head and Neck Neoplasms (drug therapy, genetics, immunology)
• Humans
• Killer Cells, Natural (drug effects, pathology)
• Male
• Middle Aged
• Prognosis
• T-Lymphocytes, Regulatory (drug effects, metabolism, pathology)
• Transforming Growth Factor beta (biosynthesis)