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Targeting Conventional T Cells in Epithelial Cancer: From Priming to Therapy

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (1 November 2021) | Viewed by 17061

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Special Issue Editors

Dr. Graham Leggatt

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Guest Editor

Faculty of Medicine, The University of Queensland Diamantina Institute, Woolloongabba, QLD, Australia
Interests: CD8 T cells; T cell functional activity; skin immunology; tumour immunology
Special Issues, Collections and Topics in MDPI journals

Dr. Jazmina Libertad Gonzalez Cruz

E-Mail Website
Guest Editor

Faculty of Medicine, The University of Queensland Diamantina Institute, Woolloongabba, QLD, Australia
Interests: T-cell epitopes; tumour vaccine; cancer immunotherapies; precision medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tumour-infiltrating lymphocytes represent a positive prognostic factor in many epithelial tumours. A role for conventional alpha beta T cells in tumour clearance has been clearly identified in many preclinical trials of tumour immunotherapy, and yet, far less is understood about their activity in human tumours. T cells must first be activated to tumour antigens in the secondary lymphoid organs, differentiate to effector T cell function, traffic to the tumour mass, operate locally in an often-unfavourable tumour microenvironment and establish long-lived memory.

This Special Issue will focus on all the attributes of conventional T cells which contribute to successful epithelial tumour clearance from identification of tumour antigens to chemokine-directed trafficking to optimal T cell function within the tumour and memory development.

Dr. Graham Leggatt
Dr. Jazmina Libertad Gonzalez Cruz
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

tumour antigens
T cell trafficking
checkpoint therapy
tumour vaccines
tumour escape
CAR T cells
T cell memory

Published Papers (6 papers)

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Research

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12 pages, 4113 KiB

Open AccessArticle

Thymic Stromal Lymphopoietin Induction Suppresses Lung Cancer Development

by Ranya Guennoun, Jennet Hojanazarova, Kathryn E. Trerice, Marjan Azin, Matthew T. McGoldrick, Erik B. Schiferle, Michael P. Stover and Shadmehr Demehri

Cancers 2022, 14(9), 2173; https://doi.org/10.3390/cancers14092173 - 27 Apr 2022

Cited by 4 | Viewed by 2039

Abstract

Lung cancer is the leading cause of cancer deaths in the United States and across the world. Immunotherapies, which activate tumor-infiltrating cytotoxic T lymphocytes, have demonstrated efficacy for the treatment of advanced-stage lung cancer. However, the potential for harnessing the immune system against the early stages of lung carcinogenesis to prevent cancer development and recurrence remains unexplored. Using a mouse model of lung adenocarcinoma, we investigated the effects of thymic stromal lymphopoietin (TSLP) induction on early cancer development in the lungs. Herein, we demonstrate that systemic TSLP induction suppressed spontaneous lung cancer development in Kras^G12D mice. TSLP drove a significant CD4⁺ T cell response to block lung cancer progression from atypical alveolar hyperplasia to adenocarcinoma. Our findings suggest that TSLP can be used in the early stages of lung cancer development to trigger a lasting immunity in the tissue and prevent the development of advanced disease. Full article

(This article belongs to the Special Issue Targeting Conventional T Cells in Epithelial Cancer: From Priming to Therapy)

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21 pages, 7527 KiB

Open AccessArticle

IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3⁺ CD8⁺ T Cells to Drive Squamous Cell Carcinoma Regression

by Zhen Zeng, Margaret Veitch, Gabrielle A. Kelly, Zewen K. Tuong, Jazmina G. Cruz, Ian H. Frazer and James W. Wells

Cancers 2021, 13(9), 2131; https://doi.org/10.3390/cancers13092131 - 28 Apr 2021

Cited by 8 | Viewed by 2517

Abstract

Ultraviolet (UV) radiation-induced tumours carry a high mutational load, are highly immunogenic, and often fail to grow when transplanted into normal, syngeneic mice. The aim of this study was to investigate factors critical for the immune-mediated rejection of cutaneous squamous cell carcinoma (SCC). In our rejection model, transplanted SCC establish and grow in mice immunosuppressed with tacrolimus. When tacrolimus is withdrawn, established SCC tumours subsequently undergo immune-mediated tumour rejection. Through the depletion of individual immune subsets at the time of tacrolimus withdrawal, we established a critical role for CD8⁺ T cells, but not CD4⁺ T cells, γδ T cells, or NK cells, in driving the regression of SCC. Regression was critically dependent on IFN-γ, although IFN-γ was not directly cytotoxic to SCC cells. IFN-γ-neutralisation abrogated SCC regression, significantly reduced CD8⁺ T cell-infiltration into SCC, and significantly impaired the secretion of CXCL9, CXCL10 and CCL5 within the tumour microenvironment. A strong positive correlation was revealed between CXCL10 expression and CD8⁺ T cell abundance in tumours. Indeed, blockade of the CXCL10 receptor CXCR3 at the time of tacrolimus withdrawal prevented CD8⁺ T cell infiltration and the regression of SCC. Chimeric models revealed an important role for immune cells as producers of IFN-γ, but not as recipients of IFN-γ signals via the IFN-γ receptor. Together, these findings suggest a key role for IFN-γ in driving the expression of chemokines within the tumour environment essential for the destruction of established SCC by CD8⁺ T cells. Full article

(This article belongs to the Special Issue Targeting Conventional T Cells in Epithelial Cancer: From Priming to Therapy)

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Review

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26 pages, 1868 KiB

Open AccessReview

Repurposing of Commercially Existing Molecular Target Therapies to Boost the Clinical Efficacy of Immune Checkpoint Blockade

by Debottam Sinha, Philip Moseley, Xuehan Lu, Quentin Wright, Brian Gabrielli, Ian H. Frazer and Jazmina L. G. Cruz

Cancers 2022, 14(24), 6150; https://doi.org/10.3390/cancers14246150 - 13 Dec 2022

Cited by 3 | Viewed by 2160

Abstract

Immune checkpoint blockade (ICB) is now standard of care for several metastatic epithelial cancers and prolongs life expectancy for a significant fraction of patients. A hostile tumor microenvironment (TME) induced by intrinsic oncogenic signaling induces an immunosuppressive niche that protects the tumor cells, limiting the durability and efficacy of ICB therapies. Addition of receptor tyrosine kinase inhibitors (RTKi) as potential modulators of an unfavorable local immune environment has resulted in moderate life expectancy improvement. Though the combination strategy of ICB and RTKi has shown significantly better results compared to individual treatment, the benefits and adverse events are additive whereas synergy of benefit would be preferable. There is therefore a need to investigate the potential of inhibitors other than RTKs to reduce malignant cell survival while enhancing anti-tumor immunity. In the last five years, preclinical studies have focused on using small molecule inhibitors targeting cell cycle and DNA damage regulators such as CDK4/6, CHK1 and poly ADP ribosyl polymerase (PARP) to selectively kill tumor cells and enhance cytotoxic immune responses. This review provides a comprehensive overview of the available drugs that attenuate immunosuppression and overcome hostile TME that could be used to boost FDA-approved ICB efficacy in the near future. Full article

(This article belongs to the Special Issue Targeting Conventional T Cells in Epithelial Cancer: From Priming to Therapy)

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19 pages, 5637 KiB

Open AccessReview

Integrin α_E(CD103)β₇ in Epithelial Cancer

by Johanna C. Hoffmann and Michael P. Schön

Cancers 2021, 13(24), 6211; https://doi.org/10.3390/cancers13246211 - 09 Dec 2021

Cited by 11 | Viewed by 3930

Abstract

Interactions of both the innate and the adaptive immune system with tumors are complex and often influence courses and therapeutic treatments in unanticipated ways. Based on the concept that CD8⁺T cells can mediate important antitumor effects, several therapies now aim to amplify their specific activity. A subpopulation of CD8⁺ tissue-resident T lymphocytes that express the α_E(CD103)β₇ integrin has raised particular interest. This receptor presumably contributes to the recruitment and retention of tumor-infiltrating immune cells through interaction with its ligand, E-cadherin. It appears to have regulatory functions and is thought to be a component of some immunological synapses. In TGF-rich environments, the α_E(CD103)β₇/E-cadherin-interaction enhances the binding strength between tumor cells and infiltrating T lymphocytes. This activity facilitates the release of lytic granule contents and cytokines as well as further immune responses and the killing of target cells. Expression of α_E(CD103)β₇ in some tumors is associated with a rather favorable prognosis, perhaps with the notable exception of squamous cell carcinoma of the skin. Although epithelial skin tumors are by far the most common tumors of fair-skinned people, there have been very few studies on the distribution of α_E(CD103)β₇ expressing cells in these neoplasms. Given this background, we describe here that α_E(CD103)β₇ is scarcely present in basal cell carcinomas, but much more abundant in squamous cell carcinomas with heterogeneous distribution. Notwithstanding a substantial number of studies, the role of α_E(CD103)β₇ in the tumor context is still far from clear. Here, we summarize the essential current knowledge on α_E(CD103)β₇ and outline that it is worthwhile to further explore this intriguing receptor with regard to the pathophysiology, therapy, and prognosis of solid tumors. Full article

(This article belongs to the Special Issue Targeting Conventional T Cells in Epithelial Cancer: From Priming to Therapy)

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16 pages, 1172 KiB

Open AccessReview

Vaccines as Priming Tools for T Cell Therapy for Epithelial Cancers

by Lana E. Kandalaft and Alexandre Harari

Cancers 2021, 13(22), 5819; https://doi.org/10.3390/cancers13225819 - 19 Nov 2021

Cited by 3 | Viewed by 2465

Abstract

Impressive progress has recently been made in the field of cancer immunotherapy with the adoptive transfer of T cells, a successful personalized strategy, and checkpoint inhibitors (CPI) having extended the survival of numerous patients. However, not all patients have been able to benefit from these innovations. A key determinant of the responsiveness to cancer immunotherapies is the presence of T cells within the tumors. These tumor-infiltrating lymphocytes (TILs) are crucial in controlling tumor growth and their activity is being potentiated by immunotherapies. Although some epithelial cancers are associated with spontaneous T-cell and B-cell responses, which makes them good candidates for immunotherapies, it remains to create strategies that would promote lymphocyte infiltration and enable sustained immune responses in immune-resistant tumors. Therapeutic cancer vaccines hold the potential of being able to render “cold”, poorly infiltrated tumors into “hot” tumors that would be receptive to cellular immunotherapies. In this review, we elaborate on the obstacles that need to be overcome and the strategies that are being explored to that end, including various types of antigen repertoires and different vaccine platforms and combinations with other available treatments. Full article

(This article belongs to the Special Issue Targeting Conventional T Cells in Epithelial Cancer: From Priming to Therapy)

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16 pages, 851 KiB

Open AccessReview

PD-1 and beyond to Activate T Cells in Cutaneous Squamous Cell Cancers: The Case for 4-1BB and VISTA Antibodies in Combination Therapy

by Quentin Wright, Jazmina L. Gonzalez Cruz, James W. Wells and Graham R. Leggatt

Cancers 2021, 13(13), 3310; https://doi.org/10.3390/cancers13133310 - 01 Jul 2021

Cited by 7 | Viewed by 3179

Abstract

Non-melanoma skin cancers (NMSC) have a higher incidence than all other cancers combined with cutaneous squamous cell carcinoma (cSCC), capable of metastasis, representing approximately 20% of NMSCs. Given the accessibility of the skin, surgery is frequently employed to treat localized disease, although certain localities, the delineation of clear margins, frequency and recurrence of tumors can make these cancers inoperable in a subset of patients. Other treatment modalities, including cryotherapy, are commonly used for individual lesions, with varying success. Immunotherapy, particularly with checkpoint antibodies, is increasingly a promising therapeutic approach in many cancers, offering the potential advantage of immune memory for protection against lesion recurrence. This review addresses a role for PD-1, 4-1BB and VISTA checkpoint antibodies as monotherapies, or in combination as a therapeutic treatment for both early and late-stage cSCC. Full article

(This article belongs to the Special Issue Targeting Conventional T Cells in Epithelial Cancer: From Priming to Therapy)

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