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T-cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer.

ABSTRACT: T-cell immunoglobulin mucin 3 (TIM3) contributes to immune suppression during progression of many cancers, but the precise role of TIM3 in head and neck squamous cell carcinoma (HNSCC) is not clearly understood. In this study, we report that TIM3 expression was significantly up-regulated in patients with HNSCC and associated with lymph node metastasis. Additionally, TIM3 expression was increased in patients with recurrent HNSCC and patients with preradiotherapy or prechemotherapy. We also characterized CD8+ T cells and CD11b+ CD33+ myeloid-derived suppressor cells (MDSCs) in human HNSCC, and found that their expression was positively correlated with TIM3 expression. To determine the underlying mechanism of TIM3 in immune response during HNSCC progression, we utilized the Tgfbr1/Pten 2cKO HNSCC mouse model with TIM3 overexpression. Treatment with anti-TIM3 monoclonal antibody effectively suppressed tumor growth through restoring effector T-cell function by targeting CD4+ TIM3+ cells and CD8+ TIM3+ cells and decreasing MDSCs. Our findings demonstrate TIM3 expression in patients with HNSCC and suggest anti-TIM3 immunotherapy as a novel therapeutic approach for effective treatment of HNSCC.

SUBMITTER: Liu JF

PROVIDER: S-EPMC5527458 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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T-cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer.

Liu Jian-Feng JF Ma Si-Rui SR Mao Liang L Bu Lin-Lin LL Yu Guang-Tao GT Li Yi-Cun YC Huang Cong-Fa CF Deng Wei-Wei WW Kulkarni Ashok B AB Zhang Wen-Feng WF Sun Zhi-Jun ZJ

Molecular oncology 20170119 2

T-cell immunoglobulin mucin 3 (TIM3) contributes to immune suppression during progression of many cancers, but the precise role of TIM3 in head and neck squamous cell carcinoma (HNSCC) is not clearly understood. In this study, we report that TIM3 expression was significantly up-regulated in patients with HNSCC and associated with lymph node metastasis. Additionally, TIM3 expression was increased in patients with recurrent HNSCC and patients with preradiotherapy or prechemotherapy. We also charac ...[more]

PMID: 28102051

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Project description:PurposeTo investigate the utility of [18F]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous cell carcinoma (HNSCC) before surgery.MethodsIn the IMCISION trial (NCT03003637), 32 patients with stage II‒IVb HNSCC were treated with neoadjuvant nivolumab with (n = 26) or without (n = 6) ipilimumab (weeks 1 and 3) before surgery (week 5). [18F]FDG-PET/CT scans were acquired at baseline and shortly before surgery in 21 patients. Images were analysed for SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG). Major and partial pathological responses (MPR and PPR, respectively) to immunotherapy were identified based on the residual viable tumour in the resected primary tumour specimen (≤ 10% and 11-50%, respectively). Pathological response in lymph node metastases was assessed separately. Response for the 2 [18F]FDG-PET-analysable patients who did not undergo surgery was determined clinically and per MR-RECIST v.1.1. A patient with a primary tumour MPR, PPR, or primary tumour MR-RECIST-based response upon immunotherapy was called a responder.ResultsMedian ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG decreased in the 8 responders and were significantly lower compared to the 13 non-responders (P = 0.05, P = 0.002, P < 0.001, and P < 0.001). A ΔMTV or ΔTLG of at least - 12.5% detected a primary tumour response with 95% accuracy, compared to 86% for the EORTC criteria. None of the patients with a ΔTLG of - 12.5% or more at the primary tumour site developed a relapse (median FU 23.0 months since surgery). Lymph node metastases with a PPR or MPR (5 metastases in 3 patients) showed a significant decrease in SUVmax (median - 3.1, P = 0.04). However, a SUVmax increase (median + 2.1) was observed in 27 lymph nodes (in 11 patients), while only 13 lymph nodes (48%) contained metastases in the corresponding neck dissection specimen.ConclusionsPrimary tumour response assessment using [18F]FDG-PET-based ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant ICB in HNSCC, outperforming the EORTC criteria, although pseudoprogression is seen in neck lymph nodes. [18F]FDG-PET could, upon validation, select HNSCC patients for response-driven treatment adaptation in future trials.Trial registrationhttps://www.Clinicaltrialsgov/ , NCT03003637, December 28, 2016.

Dataset Information

T-cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer.

Publications

T-cell immunoglobulin mucin 3 blockade drives an antitumor immune response in head and neck cancer.

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