Impact of Tumor and Immunological Heterogeneity on the Anti-Cancer Immune Response

Shembrey, Carolyn; Huntington, Nicholas D.; Hollande, Frédéric

doi:10.3390/cancers11091217

Cited by 35 publications

(30 citation statements)

References 199 publications

(210 reference statements)

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“…Overexpression of PRL3 is associated with heightened tumorigenicity and metastatic spread and is thus an attractive immunotherapeutic target (297). Blocking PRL3 with a humanized antibody (PRL3zumab) enriched NK cells in the tumor niche and promoted tumor clearance in mouse models (298). Since this study also demonstrated elevated expression of PRL3 on multiple patientderived tumor samples with little expression on the matched healthy tissue, this therapeutic approach may be beneficial for additional malignancies, and may provide enhanced specificity for immunotherapy.…”

Section: Novel Nk Cell Inhibitory Checkpoints/tumor Antigens For Blocmentioning

confidence: 69%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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Section: Novel Nk Cell Inhibitory Checkpoints/tumor Antigens For Blocmentioning

confidence: 69%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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“…Levels of TIM-3, CTLA-4, TIGIT, TOX, TOX2, and SIRT1 genes in tumor tissue were significantly higher than that of the circulation; their expressions within the TME could be induced by tumor-mediated immunosuppression [ 3 , 26 ]. These data implicate the potential importance of their elevated expression in the TME and their potential contribution to cancer progression.…”

Section: Discussionmentioning

confidence: 99%

“…Tumor tissues are heterogeneous; different tumor types and at various pathological stages can express different levels of inhibitory ICs, transcription factors and other molecules to escape immunosurveillance and promote tumor growth [26]. Therefore, we investigated whether there were any differences in mRNA levels of different genes between early and advanced disease stages (Fig.…”

Section: Comparative Analyses Of Ics and T Cell Exhaustion Markers Inmentioning

confidence: 99%

Expression of immune checkpoints and T cell exhaustion markers in early and advanced stages of colorectal cancer

Saleh

Taha

Toor

et al. 2020

Cancer Immunol Immunother

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Despite recent advances in colorectal cancer (CRC) treatment, a large proportion of patients show limited responses to therapies, especially in advanced stages. There is an urgent need to identify prognostic biomarkers and/or therapeutic targets in advanced stages, aiming to improve the efficacy of current treatments. We aimed to determine prognostic biomarkers in tumor tissue and circulation of CRC patients, with a special focus on T cell exhaustion markers. We found that mRNA levels of PD-1, TIM-3, CTLA-4, TIGIT, CD160, CD244, KLRG1, TOX2, TOX3, Ki-67, and PRDM1 were elevated in CRC tumor tissues. We also investigated differences in gene expression between early and advanced disease stages. We found that TOX and potentially TIM-3, CTLA-4, VISTA, TIGIT, KLRG1, TOX2, SIRT1, Ki-67, and Helios mRNA levels in tumor tissue were elevated in advanced disease stages, suggesting their potential roles in CRC progression. In contrast, PD-1 and CD160 levels in tumor tissue were downregulated in advanced stages. In the circulation of CRC patients, mRNA levels of PD-1, VISTA and LAG-3 were higher than those of healthy individuals. Moreover, in circulation, PD-1, CTLA-4 and TIGIT mRNA levels were reduced in advanced stages. Interestingly, levels of PD-1 in both tumor tissue and circulation were reduced in advanced stages, suggesting that targeting PD-1 in patients with advanced stages could be less effective. Altogether, these findings suggest some potential T cell exhaustion markers that could be utilized as prognostic biomarkers and/or therapeutic targets for CRC. However, further investigations and validations in larger cohorts are required to confirm these findings.

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“…There is a report focusing on the immune function of TECs. Cancer cells can evade immunosurveilance because of the abnormal circumstances caused by the tumor microenvironment [76]. Huang et al studied the α1,3-galactosyltransferase (α1,3 GT) synthesizing carbohydrate epitope Galα1-3Galβ1-4GlcNAc-R on the cell surface, which is a major barrier to xenotransplantation [77].…”

Section: For Targeting Tumor Endothelial Cellsmentioning

confidence: 99%

Targeting Tumor Endothelial Cells with Nanoparticles

Sakurai

Akita

Harashima

2019

IJMS

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Because angiogenesis is a major contributor to cancer progression and metastasis, it is an attractive target for cancer therapy. Although a diverse number of small compounds for anti-angiogenic therapy have been developed, severe adverse effects commonly occur, since small compounds can affect not only tumor endothelial cells (TECs), but also normal endothelial cells. This low selectivity for TECs has motivated researchers to develop alternate types of drug delivery systems (DDSs). In this review, we summarize the current state of knowledge concerning the delivery of nano DDSs to TECs. Their payloads range from small compounds to nucleic acids. Perspectives regarding new therapeutic targets are also mentioned.

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Impact of Tumor and Immunological Heterogeneity on the Anti-Cancer Immune Response

Cited by 35 publications

References 199 publications

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Expression of immune checkpoints and T cell exhaustion markers in early and advanced stages of colorectal cancer

Targeting Tumor Endothelial Cells with Nanoparticles

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