Role of CD8 <sup>+</sup> T lymphocyte cells: Interplay with stromal cells in tumor microenvironment

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Abstract

CD8 ⁺ T lymphocytes are pivotal cells in the host response to antitumor immunity. Tumor-driven microenvironments provide the conditions necessary for regulating infiltrating CD8 ⁺ T cells in favor of tumor survival, including weakening CD8 ⁺ T cell activation, driving tumor cells to impair immune attack, and recruiting other cells to reprogram the immune milieu. Also in tumor microenvironment, stromal cells exert immunosuppressive skills to avoid CD8 ⁺ T cell cytotoxicity. In this review, we explore the universal function and fate decision of infiltrated CD8 ⁺ T cells and highlight their antitumor response within various stromal architectures in the process of confronting neoantigen-specific tumor cells. Thus, this review provides a foundation for the development of antitumor therapy based on CD8 ⁺ T lymphocyte manipulation.

Graphical abstract

CD8 ⁺ T cells are key killing immune cells for antitumor immunity. At the same time, tumor-driven microenvironments including CAFs, TAMs, and tumor vessels can also participate to modulate infiltrating CD8 ⁺ T cells.

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Pornpimol Charoentong, Francesca Finotello, Mihaela Angelova … (2017)

The Cancer Genome Atlas revealed the genomic landscapes of human cancers. In parallel, immunotherapy is transforming the treatment of advanced cancers. Unfortunately, the majority of patients do not respond to immunotherapy, making the identification of predictive markers and the mechanisms of resistance an area of intense research. To increase our understanding of tumor-immune cell interactions, we characterized the intratumoral immune landscapes and the cancer antigenomes from 20 solid cancers and created The Cancer Immunome Atlas (https://tcia.at/). Cellular characterization of the immune infiltrates showed that tumor genotypes determine immunophenotypes and tumor escape mechanisms. Using machine learning, we identified determinants of tumor immunogenicity and developed a scoring scheme for the quantification termed immunophenoscore. The immunophenoscore was a superior predictor of response to anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death protein 1 (anti-PD-1) antibodies in two independent validation cohorts. Our findings and this resource may help inform cancer immunotherapy and facilitate the development of precision immuno-oncology.

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The Immune Landscape of Cancer

Fadlo Khuri, Natália Aredes, Jung Lee … (2018)

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

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Microenvironmental regulation of tumor progression and metastasis.

Daniela F Quail, Johanna A Joyce (2013)

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

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Author and article information

Contributors

Jian Ding

Yi Chen

Journal

Journal ID (nlm-ta): Acta Pharm Sin B

Journal ID (iso-abbrev): Acta Pharm Sin B

Title: Acta Pharmaceutica Sinica. B

Publisher: Elsevier

ISSN (Print): 2211-3835

ISSN (Electronic): 2211-3843

Publication date PMC-release: 24 April 2021

Publication date (Print): June 2021

Publication date (Electronic): 24 April 2021

Volume: 11

Issue: 6

Pages: 1365-1378

Affiliations

[a ]College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310012, China

[b ]Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

[c ]University of Chinese Academy of Sciences, Beijing 100049, China

[d ]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

[e ]Shanghai HaiHe Pharmaceutical Co., Ltd., Shanghai 201203, China

Author notes

[∗ ]Corresponding authors. jding@ 123456simm.ac.cn ychen@ 123456simm.ac.cn

Article

Publisher Item ID: S2211-3835(21)00099-X

DOI: 10.1016/j.apsb.2021.03.027

PMC ID: 8245853

PubMed ID: 34221857

SO-VID: ae0c6376-4045-4f7b-92cb-804857ea02ea

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 29 November 2020

Date revision received : 17 February 2021

Date accepted : 24 February 2021

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