Immune checkpoints and cancer development: Therapeutic implications and future directions

Mehdizadeh, Saber; Bayatipoor, Hashem; Pashangzadeh, Salar; Jafarpour, Roghayeh; Shojaei, Zeinab; Motallebnezhad, Morteza

doi:10.1016/j.prp.2021.153485

Cited by 38 publications

(25 citation statements)

References 197 publications

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“…Tumor progression is closely associated with the antitumor activity of the immune system [ 33 ]. In tumors, T cells exhaustion in terms of highly expressed immunosuppressive receptors and reduced secretion of functional cytokines is reported [ 34 ], which induces T cell inactivation and inefficiency during the antitumor process, thereby resulting in immune escape [ 35 , 36 ]. In the present study, it was revealed that the cytotoxic cells in tumor tissues are simultaneously exhausted in both quantity and function in terms of activation of TCR and apoptotic signals (Fig.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma

Gao

et al. 2022

Cell Death Dis

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Tumor heterogeneity has been associated with immunotherapy and targeted drug resistance in hepatocellular carcinoma (HCC). However, communications between tumor and cytotoxic cells are poorly understood to date. In the present study, thirty-one clusters of cells were discovered in the tumor tissues and adjacent tissues through single-cell sequencing. Moreover, the quantity and function exhaustion of cytotoxic cells was observed to be induced in tumors by the TCR and apoptosis signal pathways. Furthermore, granzyme failure of cytotoxic cells was observed in HCC patients. Importantly, the GZMA secreted by cytotoxic cells was demonstrated to interact with the F2R expressed by the tumor cells both in vivo and in vitro. This interaction induced tumor suppression and T cell-mediated killing of tumor cells via the activation of the JAK2/STAT1 signaling pathway. Mechanistically, the activation of JAK2/STAT1 signaling promoted apoptosis under the mediating effect of the LDPRSFLL motif at the N-terminus of F2R, which interacted with GZMA. In addition, GZMA and F2R were positively correlated with PD-1 and PD-L1 in tumor tissues, while the expressions of F2R and GZMA promoted PD-1 mAb-induced tumor suppression in both mouse model and HCC patients. Finally, in HCC patients, a low expression of GZMA and F2R in the tumor tissues was correlated with aggressive clinicopathological characteristics and poor prognosis. Collectively, GZMA-F2R communication inefficient induces deficient PD-1 mAb therapy and provide a completely novel immunotherapy strategy for tumor suppression in HCC patients.

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Section: Discussionmentioning

confidence: 99%

Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma

Gao

et al. 2022

Cell Death Dis

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“…Ligands of checkpoint inhibitors are also promising targets for anti-cancer therapy. PD-L1 blockade by specific antibodies, which are currently approved treatment options for a broad range of cancer types [ 186 ], has noticeable effects on the CTL compartment, with enhanced tumor-specific cytotoxic activity and release of GzmB, Prf, and IFN-γ at the tumor site [ 187 ]. A report recently published by Yang and colleagues suggests the TIM-3 ligand Galectin-9 (Gal-9) as a target for immunotherapy based on the fact that (i) high Gal-9 expression correlates with poor prognosis in multiple human cancers [ 188 ], and (ii) in PD-1 + TIM-3 + T cells, PD-1 sequesters Gal-9, hampering its binding to TIM-3 with subsequent TIM-3-dependent T cell death, thereby contributing to the persistence of the exhausted T cell population [ 189 ].…”

Section: Discussionmentioning

confidence: 99%

Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment

Capitani

Patrussi

Baldari

2021

IJMS

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Similar to Janus, the two-faced god of Roman mythology, the tumor microenvironment operates two opposing and often conflicting activities, on the one hand fighting against tumor cells, while on the other hand, favoring their proliferation, survival and migration to other sites to establish metastases. In the tumor microenvironment, cytotoxic T cells—the specialized tumor-cell killers—also show this dual nature, operating their tumor-cell directed killing activities until they become exhausted and dysfunctional, a process promoted by cancer cells themselves. Here, we discuss the opposing activities of immune cells populating the tumor microenvironment in both cancer progression and anti-cancer responses, with a focus on cytotoxic T cells and on the molecular mechanisms responsible for the efficient suppression of their killing activities as a paradigm of the power of cancer cells to shape the microenvironment for their own survival and expansion.

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“…Upregulation of checkpoint molecule ligands on tumor cells, thus, leads to T-cell exhaustion and anergy. Their blockade recently became the basis for immune-checkpoint therapies [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Challenges of CRISPR-Based Gene Editing in Primary T Cells

Rezalotfi

Fritz

Förster

et al. 2022

IJMS

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Adaptive T-cell immunotherapy holds great promise for the successful treatment of leukemia, as well as other types of cancers. More recently, it was also shown to be an effective treatment option for chronic virus infections in immunosuppressed patients. Autologous or allogeneic T cells used for immunotherapy are usually genetically modified to express novel T-cell or chimeric antigen receptors. The production of such cells was significantly simplified with the CRISPR/Cas system, allowing for the deletion or insertion of novel genes at specific locations within the genome. In this review, we describe recent methodological breakthroughs that were important for the conduction of these genetic modifications, summarize crucial points to be considered when conducting such experiments, and highlight the potential pitfalls of these approaches.

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Immune checkpoints and cancer development: Therapeutic implications and future directions

Cited by 38 publications

References 197 publications

Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma

Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma

Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment

Challenges of CRISPR-Based Gene Editing in Primary T Cells

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