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

Liu, Jian-Feng; Ma, Si‐Rui; Mao, Liang; Bu, Lin‐Lin; Yu, Guang‐Tao; Li, Yicun; Huang, Cong-Fa; Deng, Wei‐Wei; Kulkarni, Ashok B.; Zhang, Wenfeng; Sun, Zhi‐Jun

doi:10.1002/1878-0261.12029

Cited by 72 publications

(67 citation statements)

References 47 publications

(56 reference statements)

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“…TIM-3 immunohistochemistry was conducted with anti-TIM-3 rabbit monoclonal antibody clone D5D5R from Cell Signaling (Cat# 45208) as employed in other publications 21,33,49,50 , here using a Ventana Ultra automated stainer (Ventana Medical Systems) in concordance with manufacturer’s protocol. In brief, slides underwent antigen retrieval with Standard Cell Conditioning 1 reagent (Ventana Medical Systems) followed by 60 minutes of primary antibody incubation (applied at 1:50 dilution) with no heat, and visualized using a chromoMap DAB detection kit (Ventana Medical Systems).…”

Section: Methodsmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

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Section: Methodsmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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“…A previous study shows that Tim-3 overexpression induces chemoresistance to adriamycin and carboplatin in lymphoma ATN-1 cells [25]. The Tim-3 expression is increased in patients with head and neck squamous cell carcinoma after combinational chemotherapy (docetaxel, cisplatin and fluorouracil) or pre-radiotherapy [51]. And a Tim-3 antibody is able to improve the response to paclitaxel in models of triple-negative and luminal B breast cancer [6].…”

Section: Discussionmentioning

confidence: 95%

Tim-3 promotes cell aggressiveness and paclitaxel resistance through the NF-κB /STAT3 signaling pathway in breast cancer

Cong

Cui

Zhu

et al. 2020

Preprint

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virus cellular receptor 2 (HAVCR2), is a negative immune checkpoint mole cule expressed on a variety of immune cells including T cells [5], dendritic cells [6], and macrophages [7]. Accumulating evidence demonstrate that Tim-3 can reduce cell proliferation, decrease the production of effective cytokines and increase apoptosis of effector T cells, through interaction with its ligands including galectin-9, high mobility group protein B1 (HMGB1), carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM-1) and phosphatidylserine [8,9].Tim-3 is now considered as a critical mediator in cancer pro gression and attracts considerable attention as a therapeutic target. Blocking Tim-3 indeed shows some promising results in multiple preclinical cancer models [10]. More importantly, there is evidence suggesting that resistance to anti-CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) or anti-PD-1/PD-L1 inhibitors is partially by compensatory upregulation of additional immune checkpoints including Tim-3 [11]. And co-blockade of PD-1 and Tim-3 shows a significant survival advantage in a lung cancer mouse model [12]. These findings support the view that Tim-3 may be a potential target for tumour therapy.Interestingly, Tim-3 is not only expressed on immune cells but also overexpressed on many types of malignant tumours. In vitro findings revealed that Tim-3 promoted metastasis of esophageal squamous cell carcinoma (ESCC) by inducing epithelial-mesenchymal transition (EMT) via the Akt/GSK-3/Snail signalling pathway. Tim-3 knockdown markedly inhibited proliferation, migration, and invasion of ESCC cell lines [13]. Additionally, Interfering Tim-3 expression can significantly suppress osteosarcoma cell proliferation and metastasis via the NF-κB/Snail signalling pathway and EMT [14].Recently, a study in liver cancer indicated that tumour cell-intrinsic Tim-3 promotes cell proliferation via the NF-κB/IL-6/STAT3 cascade signalling axis [15]. Clinically, The ectopic expression of Tim-3 in tumour cells were correlated with more advanced pathologic T classification in non-small-cell lung carcinoma [16], lymph-vascular invasion in gastric cancer [17], lung metastasis in clear cell renal cell carcinoma [18], and lymphatic metastasis in colon cancer [9]. A meta-analysis revealed that higher expression of Tim-3 in solid tumours had significantly shorter overall survival [19]. Therefore, Tim-3 has been depicted as a prognostic indicator for those cancer patients. But contradictory results were also reported in terms of the role of Tim-3. Down-regulated Tim-3 promotes invasion and metastasis

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“…Next, we evaluated the effect of STAT4 on T cell immunosuppressive functions, which are known to promote metastasis during HNSCC. TIM3, a potent T cell suppressor of the immune response (29), was found to be significantly overexpressed in the lymph node and splenic CD4 + and splenic CD8 + T cells of metastatic Stat4 −/− mice compared to tumor bearing WT mice (Figures 2D,E). Similarly, PD-1, a negative regulator of adaptive anti-tumor immunity (30,31), was increased in lymph node and splenic CD8 + T cells and splenic CD4 + of metastatic Stat4 −/− mice compared to tumor bearing WT mice (Figures 2F,G).…”

Section: Stat4 Deficiency Promotes T Cell Immunosuppression and Diminmentioning

confidence: 99%

Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC

et al. 2020

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Head and neck squamous cell carcinoma (HNSCC) is a prevalent form of cancer with 5-years survival rates around 57%, and metastasis is a leading cause of mortality. Host-derived immunological factors that affect HNSCC tumor development and metastasis are not completely understood. We investigated the role of host-derived signal transducer and activator of transcription 4 (STAT4) during experimental HNSCC using an aggressive and metastatic HNSCC cell line, LY2, which was orthotopically injected into the buccal sulcus of wild type (WT) and STAT4 deficient (Stat4 −/−) BALB/c mice. Necropsies performed at terminal sacrifice revealed that Stat4 −/− mice displayed comparable primary tumor growth to the WT mice. However, the rate and extent of lymph node and lung metastasis among Stat4 −/− mice was significantly higher. Downstream analyses performed on primary tumors, draining lymph nodes, spleens and bone marrow revealed significant upregulation of lymphocytic immunosuppressive biomarkers as well as an accumulation of granulocytic MDSC subpopulations in draining lymph nodes of metastatic Stat4 −/− mice. Further, we observed a significant decrease in T H 1, T H 17, and cytotoxic activity in tumor bearing Stat4 −/− compared to WT mice. Our results demonstrate that STAT4 mediates resistance to HNSCC metastasis, and activation of STAT4 could potentially mitigate lymphatic metastasis in HNSCC patients.

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

Cited by 72 publications

References 47 publications

TIM-3 expression in breast cancer

TIM-3 expression in breast cancer

Tim-3 promotes cell aggressiveness and paclitaxel resistance through the NF-κB /STAT3 signaling pathway in breast cancer

Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC

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