Emerging Targets in Cancer Immunotherapy: Beyond CTLA-4 and PD-1

Assal, Amer; Kaner, Justin D.; Pendurti, Gopichand; Zang, Xingxing

doi:10.2217/imt.15.78

Cited by 47 publications

(38 citation statements)

References 145 publications

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“…(Grosso et al 2007, Assal et al 2015. LAG-3 acts as a negative regulator of T-cell activation and homeostasis (Grosso et al 2007).…”

Section: New Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…TIM-3 can also impair immune responses by promoting the expansion of myeloid-derived suppressor cells (Sakuishi et al 2011). Tumor-infiltrating CD4 and CD8 cells co-express TIM-3 and PD-1 in murine models of colon adenocarcinoma, melanoma and mammary adenocarcinoma (Assal et al 2015). In humans, TIM-3 is expressed on tumorinfiltrating lymphocytes or T cells in the peripheral blood of patients with various types of cancer such as hepatocellular cancer, cervical cancer, colorectal cancer, ovarian cancer, non-small-cell lung cancer, head and neck cancer, renal cell carcinoma, gastric cancer, esophageal cancer, prostate cancer and non-Hodgkin lymphoma (Yang et al 2012, Jie et al 2013, Yan et al 2013, Japp et al 2015, Thommen et al 2015, Cai et al 2016, Xie et al 2016.…”

Section: Lag-3 Also Called Cd223 Lag-3 Is Expressed On Activated T Cmentioning

confidence: 99%

“…When tryptophan levels are decreased, the cell cycle is arrested with the inactivation of mTOR pathway, and tryptophan metabolites lead to T-cell apoptosis and Treg cell differentiation (Assal et al 2015). One of the IDOs, IDO1, is expressed in mature dendritic cells in lymphoid tissues, some epithelial cells of the female genital tract and placental and pulmonary endothelial cells, and IDOs can also be found in lymphoid tissues of tumors such as cervical, colorectal, gastric tumors, as well as vascular cells in renal cell cancer (Theate et al 2015).…”

Section: Lag-3 Also Called Cd223 Lag-3 Is Expressed On Activated T Cmentioning

confidence: 99%

“…Tumors expressing IDO1 have a more aggressive phenotype and lead to poorer prognosis than tumors that do not express this protein (Godin-Ethier et al 2011). There are several ongoing studies investigating the effect of the IDO inhibitor indoximod both alone and in combination with other antitumoral agents (Assal et al 2015, Jiang et al 2017, Meng et al 2017, Tomek et al 2017.…”

Section: Lag-3 Also Called Cd223 Lag-3 Is Expressed On Activated T Cmentioning

confidence: 99%

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Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

Cunha

Marcello

Rocha-Santos

et al. 2017

Endocrine-Related Cancer

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Immune checkpoint inhibitors are agents that act by inhibiting the mechanisms of immune escape displayed by various cancers. The success of immune checkpoint inhibitors against several tumors has promoted a new treatment strategy in clinical oncology, and this has encouraged physicians to increase the number of patients who receive the immune checkpoint therapy. In the present article, we review the main concepts regarding immune checkpoint mechanisms and how cancer disrupts them to undergo immune escape. In addition, we describe the most essential concepts related to immune checkpoint inhibitors. We critically review the literature on preclinical and clinical studies of the immune checkpoint inhibitors as a treatment option for thyroid cancer, ovarian carcinoma, pancreatic adenocarcinoma, adrenocortical carcinoma and neuroendocrine tumors. We present the challenges and the opportunities of using immune checkpoint inhibitors against these endocrine malignancies, highlighting the breakthroughs and pitfalls that have recently emerged.

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“…(Grosso et al 2007, Assal et al 2015. LAG-3 acts as a negative regulator of T-cell activation and homeostasis (Grosso et al 2007).…”

Section: New Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Lag-3 Also Called Cd223 Lag-3 Is Expressed On Activated T Cmentioning

confidence: 99%

Section: Lag-3 Also Called Cd223 Lag-3 Is Expressed On Activated T Cmentioning

confidence: 99%

Section: Lag-3 Also Called Cd223 Lag-3 Is Expressed On Activated T Cmentioning

confidence: 99%

See 2 more Smart Citations

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

Cunha

Marcello

Rocha-Santos

et al. 2017

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…21,22 Moreover, the well-known B7-1 or B7-2/CTLA-4 and PD-L1/PD-1 pathways are promising targets for tumor immune checkpoint therapy. 5,23 However, the systemic alteration of these families has not been defined in CRC.…”

Section: Introductionmentioning

confidence: 99%

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

Tang

Liu

et al. 2018

OncoImmunology

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Immunotherapy is reportedly effective in a subset of colorectal cancers (CRCs) with high microsatellite instability (MSI-H). Exploring the expression patterns and clinical values of immunologic molecules is critical in defining the specific responsive candidates. Here, we performed comprehensive molecular profiling of the B7 and TNFR family genes across 6 CRC datasets with over 1,000 patients’ details using cBioPortal TCGA data. About 20% of patients had B7 and TNFR family gene alterations. The frequency of B7 gene mutations (2.2%–5%) were similar to copy number alterations (0.53%–5.46%). TNFR amplifications were relatively more common (5.45–11.32%) than that of B7 (0.09–2.73%). B7 and TNFR gene mRNAs were upregulated in 26% of cases (102/379) and 16% of cases (61/379), respectively. The mRNA levels of B7 and TNFR genes were inversely correlated with promoter methylation status. Clinically, both B7-H3 and TNFSF7 mRNA overexpression were associated with unfavorable clinical outcomes, and the B7-H3 expression was increased gradually in cases with gene amplifications. Moreover, patients with MSI-H had significantly higher PD-L1 or PD-1 expression. Most importantly, in MSI-H group, patients with PD-L1 or PD-1 upregulation had poorer survivals than those with PD-L1/PD-1 downregulation. This is the first study drawing the immune landscapes of the co-stimulator B7 and TNFR families in CRC and showing that MSI-H patients with PD-1/PD-L1 upregulation are associated with poor clinical outcomes, providing potential markers to stratify patients responsive to immune checkpoint therapy.

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Engineered Small Extracellular Vesicles as a FGL1/PD‐L1 Dual‐Targeting Delivery System for Alleviating Immune Rejection

Tsai

Liu

et al. 2021

Advanced Science

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There is an urgent need for developing new immunosuppressive agents due to the toxicity of long‐term use of broad immunosuppressive agents after organ transplantation. Comprehensive sample analysis revealed dysregulation of FGL1/LAG‐3 and PD‐L1/PD‐1 immune checkpoints in allogeneic heart transplantation mice and clinical kidney transplant patients. In order to enhance these two immunosuppressive signal axes, a bioengineering strategy is developed to simultaneously display FGL1/PD‐L1 (FP) on the surface of small extracellular vesicles (sEVs). Among various cell sources, FP sEVs derived from mesenchymal stem cells (MSCs) not only enriches FGL1/PD‐L1 expression but also maintain the immunomodulatory properties of unmodified MSC sEVs. Next, it is confirmed that FGL1 and PD‐L1 on sEVs are specifically bound to their receptors, LAG‐3 and PD‐1 on target cells. Importantly, FP sEVs significantly inhibite T cell activation and proliferation in vitro and a heart allograft model. Furthermore, FP sEVs encapsulated with low‐dose FK506 (FP sEVs@FK506) exert stronger effects on inhibiting T cell proliferation, reducing CD8+ T cell density and cytokine production in the spleens and heart grafts, inducing regulatory T cells in lymph nodes, and extending graft survival. Taken together, dual‐targeting sEVs have the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection.

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Emerging Targets in Cancer Immunotherapy: Beyond CTLA-4 and PD-1

Cited by 47 publications

References 145 publications

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

Engineered Small Extracellular Vesicles as a FGL1/PD‐L1 Dual‐Targeting Delivery System for Alleviating Immune Rejection

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