scholarly journals B7-H5 blockade enhances CD8+ T-cell-mediated antitumor immunity in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiayu Wang ◽  
Hongya Wu ◽  
Yanjun Chen ◽  
Jinghan Zhu ◽  
Linqing Sun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Inverse Correlation ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
T Cell Infiltration

AbstractNegative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlated with the lymph node involvement, AJCC stage, and survival of CRC patients. A significant inverse correlation was also observed between B7-H5 expression and CD8+ T-cell infiltration in CRC tissues. Kaplan−Meier analysis showed that patients with high B7-H5 expression and low CD8+ T-cell infiltration had the worst prognosis in our cohort of CRC patients. Remarkably, both high B7-H5 expression and low CD8+ T infiltration were risk factors for overall survival. Additionally, B7-H5 blockade using a B7-H5 monoclonal antibody (B7-H5 mAb) effectively suppressed the growth of MC38 colon cancer tumors by enhancing the infiltration and Granzyme B production of CD8+ T cells. Importantly, the depletion of CD8+ T cells obviously abolished the antitumor effect of B7-H5 blockade in the MC38 tumors. In sum, our findings suggest that B7-H5 may be a valuably prognostic marker for CRC and a potential target for CRC immunotherapy.

scholarly journals Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 57
Author(s):  
Man-Chin Chen ◽  
Christian Ronquillo Pangilinan ◽  
Che-Hsin Lee
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
Programmed Death Ligand 1 ◽  
T Cell Infiltration ◽  
Programmed Death

Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.

Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3061-3061 ◽  
Author(s):  
Mark Selby ◽  
John Engelhardt ◽  
Li-Sheng Lu ◽  
Michael Quigley ◽  
Changyu Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cell Infiltration ◽  
Preclinical Models ◽  
Concurrent Treatment ◽  
T Cell Infiltration ◽  
Synergistic Antitumor Activity

3061 Background: Interaction of immune checkpoint molecules PD-1 and CTLA-4 and their respective ligands attenuates antitumor T cell responses. In clinical studies, PD-1 blocking antibody (Ab) nivolumab (BMS-936558) or the CTLA-4 blocking Ab ipilimumab result in durable responses in multiple human malignancies. We describe the evaluation of concurrent treatment with anti-PD-1 and anti-CTLA-4 mAbs in preclinical models. Methods: Antitumor activity of treatment with murine homologs of anti-PD-1 (4H2-mIgG1) and anti-CTLA-4 (9D9-mIgG2b) was evaluated in MC38, a murine colon adenocarcinoma model. The effects of concurrent treatment on T cell infiltration of tumors, tumoral expression of PD-L1 and cytokine levels were explored. The preclinical safety profile of concurrent nivolumab + ipilimumab was assessed in a cynomolgus macaque model. Results: Concurrent treatment of MC38 tumors with 4H2-mIgG1 + 9D9-mIgG2b (10 mg/kg Q3d x 3) results in synergistic antitumor activity whereas efficacy with sequential dosing was similar to either agent alone. With concurrent treatment, dose reductions of one Ab relative to a fixed dose of the other resulted in retention of some antitumor activity. Anti-PD-1 enhanced CD8+ T cell infiltration of MC38 tumors and increased tumor PD-L1 expression. Anti-CTLA-4 treatment increased intratumoral CD8+ T cells and reduced intratumoral T regulatory cells. While concurrent treatment did not result in further increases in T cell infiltration, it increased expression of intratumoral cytokines. Anti-PD-1 resulted in down regulation of cell surface and intracellular levels of PD-1 in CD8+ T cells. In cynomolgus macaques, concurrent nivolumab + ipilimumab resulted in dose-dependent gastrointestinal toxicities (diarrhea; body weight loss) not observed in earlier cynomolgus studies with nivolumab and rarely with ipilimumab. These preclinical observations provided the rationale for a dose escalation trial (NCT01024231) of combined nivolumab + ipilimumab in advanced melanoma. Conclusions: Concurrent treatment with anti-PD-1/anti-CTLA-4 resulted in synergistic antitumor activity in preclinical models and supports the evaluation of the combination in clinical studies.

scholarly journals Immunogenomic profile of colorectal cancer response to immune checkpoint blockade

2020 ◽  
Author(s):  
Michele Bortolomeazzi ◽  
Mohamed Reda Keddar ◽  
Lucia Montorsi ◽  
Amelia Acha-Sagredo ◽  
Lorena Benedetti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Critical Threshold ◽  
Mutational Burden ◽  
Antigen Presenting

To dissect the determinants of the heterogeneous response of colorectal cancer (CRC) to immune checkpoint blockade, we profile tumour and immune infiltrates of 721 cancer regions from 29 patients treated with Pembrolizumab or Nivolumab. Combining multi-regional whole exome, RNA and T-cell receptor sequencing we show that anti-PD1 agents are most effective in CRCs with high mutational burden and low activation of the WNT pathway. However, above a critical threshold defining the hypermutated phenotype, response is no longer associated with mutational burden but rather with high clonality of immunogenic mutations, expanded T cells and active immune escape mechanisms. Using high-dimensional imaging mass cytometry and multiplexed immunofluorescence, we observe that responsive hypermutated CRCs are rich in cytotoxic and proliferating PD1-expressing CD8 infiltrates interacting with high-density clusters of PDL1-expressing antigen presenting macrophages. We propose that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages thus promoting their expansion in intra-tumour niches.

PAX5 haploinsufficiency induces low T cell infiltration in the cancer microenvironment via reduced chemokines

2021 ◽  
Vol 21 ◽  
Author(s):  
Lei Wang ◽  
Xue Liang ◽  
Mi Liang ◽  
Dang Li ◽  
Jia Gu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Gene Editing ◽  
Immune Escape ◽  
Cell Infiltration ◽  
Loss Of Function ◽  
Wild Type ◽  
T Cell Infiltration ◽  
Wild Type Control

Aims: To investigate the effects of PAXT mutations on tumor immunity. Background: Loss of function of PAX5 plays a key role in PAX5 mutation tumor. Objective: PAX5 haploinsufficiency promoting tumorigenesis is related to immune escape, but there was no report about mechanisms of PAX5 mutation inducing tumor immunological escape. Method: We constructed the PAX5 haplodeletion A20 cell lines using gene-editing technology, built allografted A20 tumor models and evaluated the effect of PAX5 haplodeletion on T cells and chemokines in the tumor microenvironment (TME). Result: Our results from different methods indicated percentages of CD3+ CD4+ T cells and CD3+ CD8+ T cells in TME of PAX5 haplodeletion clones decreased significantly compared with that of PAX5 wild type control. Several chemokines, such as Ccl2, Ccl4, Cxcl9 and Cxcl10, in TME of PAX5. Conclusion: Our study showed that PAX5 haploinsufficiency induced low T cell infiltration in TME using decreased chemokines.

scholarly journals RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade

2018 ◽  
Vol 26 (11) ◽  
pp. 2567-2579 ◽  
Author(s):  
Shanthi Ganesh ◽  
Xue Shui ◽  
Kevin P. Craig ◽  
Jihye Park ◽  
Weimin Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration

2020 ◽  
Vol 8 (2) ◽  
pp. e001224 ◽  
Author(s):  
Hussein Sultan ◽  
Juan Wu ◽  
Valentyna I Fesenkova ◽  
Aaron E Fan ◽  
Diane Addis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Cell Infiltration ◽  
Mouse Tumor ◽  
Type I ◽  
Antitumor Effects ◽  
Cell Therapies ◽  
T Cell Infiltration

BackgroundImmunotherapies, such as immune checkpoint inhibitors and adoptive cell therapies, have revolutionized cancer treatment and resulted in complete and durable responses in some patients. Unfortunately, most immunotherapy treated patients still fail to respond. Absence of T cell infiltration to the tumor site is one of the major obstacles limiting immunotherapy efficacy against solid tumors. Thus, the development of strategies that enhance T cell infiltration and broaden the antitumor efficacy of immunotherapies is greatly needed.MethodsWe used mouse tumor models, genetically deficient mice and vascular endothelial cells (VECs) to study the requirements for T cell infiltration into tumors.ResultsA specific formulation of poly-IC, containing poly-lysine and carboxymethylcellulose (PICLC) facilitated the traffic and infiltration of effector CD8 T cells into the tumors that reduced tumor growth. Surprisingly, intratumoral injection of PICLC was significantly less effective in inducing tumor T cell infiltration and controlling growth of tumors as compared with systemic (intravenous or intramuscular) administration. Systemically administered PICLC, but not poly-IC stimulated tumor VECs via the double-stranded RNA cytoplasmic sensor MDA5, resulting in enhanced adhesion molecule expression and the production of type I interferon (IFN-I) and T cell recruiting chemokines. Expression of IFNαβ receptor in VECs was necessary to obtain the antitumor effects by PICLC and IFN-I was found to directly stimulate the secretion of T cell recruiting chemokines by VECs indicating that this cytokine-chemokine regulatory axis is crucial for recruiting effector T cells into the tumor parenchyma. Unexpectedly, these effects of PICLC were mostly observed in tumors and not in normal tissues.ConclusionsThese findings have strong implications for the improvement of all types of T cell-based immunotherapies for solid cancers. We predict that systemic administration of PICLC will improve immune checkpoint inhibitor therapy, adoptive cell therapies and therapeutic cancer vaccines.

scholarly journals Global Pattern of CD8+ T-Cell Infiltration and Exhaustion in Colorectal Cancer Predicts Cancer Immunotherapy Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Sun Tian ◽  
Fulong Wang ◽  
Rongxin Zhang ◽  
Gong Chen
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cell Infiltration ◽  
Specific Method ◽  
T Cell Exhaustion ◽  
Global Pattern ◽  
Cell Exhaustion ◽  
T Cell Infiltration

Background: The MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. Thus, we developed a colorectal cancer-specific method that predicts cancer immunotherapy response.Methods: We used gene expression data of 454 samples (MSI = 131, MSI-L = 23, MSS = 284, and Unknown = 16) and developed a TMEPRE method that models signatures of CD8+ T-cell infiltration and CD8+ T-cell exhaustion states in the tumor microenvironment of colorectal cancer. TMEPRE model was validated on three RNAseq datasets of melanoma patients who received pembrolizumab or nivolumab and one RNAseq dataset of purified CD8+ T cells in different exhaustion states.Results: TMEPRE showed predictive power in three datasets of anti-PD1-treated patients (p = 0.056, 0.115, 0.003). CD8+ T-cell exhaustion component of TMEPRE model correlates with anti-PD1 responding progenitor exhausted CD8+ T cells in both tumor and viral infection (p = 0.048, 0.001). The global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characteristics that can potentially benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed insufficient tumor-infiltrating CD8+ T cells and 50% showed terminal exhaustion of CD8+ T cells. These terminally exhausted CD8+ T cells coexisted with signatures of myeloid-derived suppressor cells in colorectal cancer.Conclusion: TMEPRE is a colorectal cancer-specific method. It captures characteristics of CD8+ T-cell infiltration and CD8+ T-cell exhaustion state and predicts cancer immunotherapy response. A subset of MSS patients could potentially benefit from anti-PD1 treatment. Anti-PD1 resistance MSI patients with insufficient infiltration of CD8+ T cells or terminal exhaustion of CD8+ T cells need different treatment strategies.

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