Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas

Zhou, Guoying; Sprengers, Dave; Boor, Patrick P.C.; Doukas, Michail; Schutz, Hannah M.; Mancham, Shanta; Pedroza-González, Alexander; Polak, Wojciech; Jonge, Jeroen de; Gaspersz, M.; Dong, Haidong; Thielemans, Kris; Pan, Qiuwei; IJzermans, Jan N.M.; Bruno, Marco J.; Kwekkeboom, Jaap

doi:10.1053/j.gastro.2017.06.017

Cited by 336 publications

(324 citation statements)

References 52 publications

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“…Similar to what we reported in hepatocellular carcinoma, 44 intra-tumoral CD8 + CTL and CD4 + Th in MMR-proficient LM-CRC displayed increased expression of PD-1, TIM3, CTLA4 and/or LAG3 compared to their counterparts in TFL and blood. In addition, we found selectively enhanced expression of PD-1 and TIM3 on intra-tumoral Treg (Fig.…”

Section: Discussionsupporting

confidence: 89%

“…Similar to what we reported in hepatocellular carcinoma, 44 intra-tumoral CD4 + Th and CD8 + CTL expressing any of the four inhibitory receptors showed a more activated status but produced reduced or similar levels of effector cytokines than their counterparts not expressing the corresponding inhibitory receptor (Fig. 4).…”

Section: Discussionsupporting

confidence: 87%

“…This result also contrasts to our recent observation that ex vivo responses of TIL isolated from hepatocellular carcinomas can be invigorated by TIM3 blockade. 44 This difference may relate to the lower expression of galectin 9 on APC subsets in LM-CRC compared to hepatocellular carcinomas.…”

Section: Discussionmentioning

confidence: 99%

“…Simultaneously TIL isolated from LM-CRC were kept at 4°C in complete medium overnight. Thereafter TIL were labeled with 0.1 µM carboxyfluorescein diacetate succinimidyl ester (CFSE, Invitrogen), and 10 5 TIL were co-cultured with autologous mDC preloaded with or without tumor lysates or normal liver lysates at an mDC: TIL ratio of 1:5, in the presence or absence of 10 μg/ml antagonistic monoclonal antibodies against human PD-L1 (clone 5H1, kindly provided by Dr. Haidong Dong, Mayo Clinic College of Medicine, 59 ) TIM3 (clone F38-2E2, Biolegend, San Diego, USA, 44 ) LAG3 (clone 17B4, AdipoGen, Liestal, Switzerland 44 ) or CTLA4 (clone BNI3, Beckman Coulter, Marseille, France, 63 ) in 200 µl complete medium in each well of a 96-well round-bottom culture plate. After six days, cells were restimulated with PMA (40 ng/mL) and ionomycin (1 µg/mL) for five hours in the presence of 5 µg/mL brefeldin for the last four hours.…”

Section: Methodsmentioning

confidence: 99%

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Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

et al. 2018

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Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

et al. 2018

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“…We showed that the concurrent expression of genes correlated to cytotoxic activity and inhibitory checkpoint genes in cluster T1, characterized by longer TTR. This observation is consistent with the enhanced expression of inhibitory receptors on TAA-specific lymphocytes infiltrating HCC [32] and other tumors [33]. In this context, the upregulation of inhibitory receptors may represent a regulatory mechanism aimed at preventing overactivation of the antitumor immune response [32].…”

Section: Discussionsupporting

confidence: 78%

Immune Gene Expression Profile in Hepatocellular Carcinoma and Surrounding Tissue Predicts Time to Tumor Recurrence

et al. 2018

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Background: The antitumor immune response may play a major role in the clinical outcome of hepatocellular carcinoma (HCC). We characterized the liver immune microenvironment by direct hybridization of RNA extracted from HCC and nontumorous tissues. Methods: RNA was extracted from frozen liver tissue samples of HCC (T; n = 30) and nontumorous tissues (NT; n = 33) obtained from 38 patients. Matched samples were available for 25 patients. The immune gene expression profile was analyzed with the nCounter GX Human Immunology v2 system (NanoString Technologies), which detects the expression levels of 579 immune response-related genes simultaneously. Results: Since the immune gene expression profile of T and NT tissues was significantly different, the prognostic relevance of the liver immune microenvironment was evaluated in the T and NT samples separately. Unsupervised clustering detected two main clusters of immune gene expression both in T and in NT liver samples. In both cases, the expression clusters identified groups of patients with a significantly different median time to HCC recurrence (TTR) but similar overall survival. Based on T tissue, two groups with median TTR of 19 and 127 months, respectively, were detected (p < 0.005). Expression of genes related to T-cell activation was associated with longer TTR. The analysis of NT tissue discriminated subsets of patients with median TTR of 22 and 68 months (p < 0.05). In contrast to T tissue, a predominant inflammatory immune environment was associated with shorter TTR. Conclusions: Immune gene expression profiles predictive of TTR could be identified both in HCC and in adjacent cirrhotic tissues. Longer TTR was associated with overexpression in T tissue and downregulation in NT tissue of the immune response and of inflammation-related genes.

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Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution

Dóra

Rivard

et al. 2020

Molecular Oncology

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Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)‐high and NE‐low subtypes showing ‘immune desert’ and ‘immune oasis’ phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross‐sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early‐stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE‐associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin‐fixed paraffin‐embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3‐dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45+ cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8+ effector T‐cell infiltration (P = 0.003) in NE‐low vs NE‐high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE‐low primary tumors (vs NE‐high, P < 0.05). We also found significantly higher MHC II expression by malignant cells in NE‐low (vs NE‐high, P = 0.004) tumors. TIM3 expression was significantly increased in NE‐low (vs NE‐high, P < 0.05) tumors and in LN metastases (vs primary tumors, P < 0.05). To our knowledge, this is the first human study that demonstrates in situ that NE‐low SCLCs are associated with increased immune cell infiltration compared to NE‐high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE‐low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies.

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Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas

Cited by 336 publications

References 52 publications

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

Immune Gene Expression Profile in Hepatocellular Carcinoma and Surrounding Tissue Predicts Time to Tumor Recurrence

Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution

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