Co-stimulatory and co-inhibitory pathways in cancer immunotherapy

O'Neill, R.; Cao, Xuefang

doi:10.1016/bs.acr.2019.03.003

Cited by 74 publications

(45 citation statements)

References 286 publications

(303 reference statements)

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“…The antigen-specific T cells are able to identify Major Histocompatibility Complex (MHC) conjugated tumor antigen and initiate the first activation signal pathway. Then, the costimulatory ligands on the APCs interact with the T cells' costimulatory receptors, driving the activation of effector cells, provoking a potent antitumor response ultimately [5,29,30]. Furthermore, the interaction of costimulatory ligands and receptors also contributes to the activation of Natural Killing (NK) cells and promotes cytokine production [4,11].…”

Section: Discussionmentioning

confidence: 99%

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Antitumor Activities of Immune Costimulatory Molecules of TNF Superfamily in Colorectal and Lung Cancers

Gui¹,

Wang²,

Pan³

et al. 2021

austinjcancerclinres

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Cancer immunotherapy has emerged as a promising treatment that utilizes the innate or adaptive immunity to generate a robust killing of malignant cells. However, only a limited number of cancer patients showed responsiveness to immunotherapies such as checkpoint inhibitors, suggesting the need for potent alternative strategies. In the present study, we explored the therapeutic potentials of costimulatory molecules including TNF superfamily member 4 (TNFSF4), member 9 (TNFSF9), and member 18 (TNFSF18). In tumor samples from human colorectal and lung cancer patients, expression of these factors positively correlated with lymphocyte infiltration and expression of several immune effector genes. In syngeneic mouse tumor models, overexpression of the TNF superfamily costimulatory factors in murine colorectal or lung cancer cells significantly suppressed tumor progression. Especially, TNFSF9 and 18 showed stronger antitumor effects than TNFSF4. Together, our study demonstrated the great potential of cancer immunotherapy targeting these immune costimulatory molecules.

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Section: Discussionmentioning

confidence: 99%

“…Costimulatory molecules play a crucial role in effector immune response, providing costimulatory signals for immune cell proliferation, differentiation, activation, and cytokine production [4,5]. Moreover, costimulatory pathways are essential in driving effective antitumor immunity [6].…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activities of Immune Costimulatory Molecules of TNF Superfamily in Colorectal and Lung Cancers

Gui¹,

Wang²,

Pan³

et al. 2021

austinjcancerclinres

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show abstract

“…They play vital role in regulating T-cell proliferation, survival, and cytotoxic functions [ 81 ]. Because of this, their use and activation is currently extensively researched for boosting cancer immunotherapies [ 82 ], including CAR-T therapies, specifically for 4-1BB and OX40 [ 82 , 83 ]. The inclusion of the signaling domain of 4-1BB in chimeric antigen receptor-T (CAR-T) cells can enhance T-cell persistence and cytotoxic functions, which correlate with reducing tumor burden when adoptively transferred to tumor-bearing mice [ 84 ].…”

Section: Key Mechanism Of T-cell Activation and Inhibition And Its Use In Immunotherapymentioning

confidence: 99%

Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy

Gavali

Liu

Paolino

2021

IJMS

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The advent of T-cell-based immunotherapy has remarkably transformed cancer patient treatment. Despite their success, the currently approved immunotherapeutic protocols still encounter limitations, cause toxicity, and give disparate patient outcomes. Thus, a deeper understanding of the molecular mechanisms of T-cell activation and inhibition is much needed to rationally expand targets and possibilities to improve immunotherapies. Protein ubiquitination downstream of immune signaling pathways is essential to fine-tune virtually all immune responses, in particular, the positive and negative regulation of T-cell activation. Numerous studies have demonstrated that deregulation of ubiquitin-dependent pathways can significantly alter T-cell activation and enhance antitumor responses. Consequently, researchers in academia and industry are actively developing technologies to selectively exploit ubiquitin-related enzymes for cancer therapeutics. In this review, we discuss the molecular and functional roles of ubiquitination in key T-cell activation and checkpoint inhibitory pathways to highlight the vast possibilities that targeting ubiquitination offers for advancing T-cell-based immunotherapies.

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“…Hence, there is an urgent need to overcome the CRC associated immunosuppression, which would enable the proportion of patients who benefit from PD-1/PD-L1 blockade to be expanded. Numerous preclinical studies have indicated that the combination of ICIs with other treatments such as chemotherapy, radiation therapy and targeted therapy could be a promising approach to overcome immunosuppression and improve therapeutic efficacy (O'Neill and Cao, 2019).…”

Section: Introductionmentioning

confidence: 99%

Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma

Peng

Zhao

et al. 2021

Front. Cell Dev. Biol.

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Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. However, the overall response rate to immune checkpoint inhibitor therapy for many cancers is only between 20 and 40%, and even less for colorectal cancer (CRC) patients. Thus, there is an urgent need to develop an efficient immunotherapeutic strategy for CRC. Here, we developed a novel CRC combination therapy consisting of a multiple receptor tyrosine kinase inhibitor (Foretinib) and anti-PD-1 antibody. The combination therapy significantly inhibited tumor growth in mice, led to improved tumor regression without relapse (83% for CT26 tumors and 50% for MC38 tumors) and prolonged overall survival. Mechanistically, Foretinib caused increased levels of PD-L1 via activating the JAK2-STAT1 pathway, which could improve the effectiveness of the immune checkpoint inhibitor. Moreover, the combination therapy remodeled the tumor microenvironment and enhanced anti-tumor immunity by further increasing the infiltration and improving the function of T cells, decreasing the percentage of tumor-associated macrophages (TAMs) and inhibiting their polarization toward the M2 phenotype. Furthermore, the combination therapy inhibited the metastasis of CT26-Luc tumors to the lung in BALB/c mouse by reducing proportions of regulatory T-cells, TAMs and M2 phenotype TAMs in their lungs. This study suggests that a novel combination therapy utilizing both Foretinib and anti-PD-1 antibody could be an effective combination strategy for CRC immunotherapy.

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Co-stimulatory and co-inhibitory pathways in cancer immunotherapy

Cited by 74 publications

References 286 publications

Antitumor Activities of Immune Costimulatory Molecules of TNF Superfamily in Colorectal and Lung Cancers

Antitumor Activities of Immune Costimulatory Molecules of TNF Superfamily in Colorectal and Lung Cancers

Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy

Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma

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