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Potential effect of tumor-specific Treg-targeted antibodies in the treatment of human cancers: A bioinformatics analysis.

ABSTRACT: One of the mechanisms of tumor rejection in immune-modulatory treatments is antibody-dependent cell-mediated cytotoxicity (ADCC) of regulatory T cells (Tregs) that infiltrate tumors in which cells expressing activating Fc? receptors (Fc?Rs) are present. Our objective was to identify, through a bioinformatics analysis, Treg marker(s) expressed at the highest levels in nine types of human cancers, in order to determine the best targets for ADCC-inducing antitumor antibodies. We analyzed the mRNA levels of 24 surface Treg markers evaluated by the Affymetrix Human Genome U133 Plus 2.0 Array in 5728 cancer samples obtained via the Genevestigator v3 suite. Our analysis was based on overexpression of markers in tumors as compared to healthy tissues (HTs) and correlation between overexpression of the markers and the tumor suppressive microenvironment. Moreover, we evaluated tumoral infiltration of activating Fc?R-expressing cells and calculated the ADCC index for each overexpressed marker, as an indicator of whether the marker was a good target for ADCC induction in tumor-infiltrating Tregs. The results demonstrated that the ADCC strategy is unlikely to succeed in colorectal, liver, prostate and ovarian cancers. Moreover, we identified nine Treg markers that could be targeted in the other tumors: 4-1BB, CD39, galectin-9, GITR, IL-21R, LAP, neuropilin-1, TIGIT and TNFR2. GITR and TIGIT were the only markers that could be potentially useful as targets for the treatment of three cancers: non-squamous and squamous NSCLC and breast infiltrating ductal carcinoma. LAP, neuropilin-1 and CD39 presented as good targets in the treatment of renal cell carcinoma. Our findings may have value for the development of new anti-tumor antibodies.

SUBMITTER: Cari L

PROVIDER: S-EPMC5749671 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Potential effect of tumor-specific Treg-targeted antibodies in the treatment of human cancers: A bioinformatics analysis.

Cari Luigi L Nocentini Giuseppe G Migliorati Graziella G Riccardi Carlo C

Oncoimmunology 20171109 2

One of the mechanisms of tumor rejection in immune-modulatory treatments is antibody-dependent cell-mediated cytotoxicity (ADCC) of regulatory T cells (Tregs) that infiltrate tumors in which cells expressing activating Fcγ receptors (FcγRs) are present. Our objective was to identify, through a bioinformatics analysis, Treg marker(s) expressed at the highest levels in nine types of human cancers, in order to determine the best targets for ADCC-inducing antitumor antibodies. We analyzed the mRNA l ...[more]

PMID: 29308313

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Project description:AbstractIn an earlier publication, a binary classification of chronic diseases has been proposed. Chronic diseases were classified as “high Treg” or “low Treg” diseases depending on whether the pro-inflammatory or the anti-inflammatory arms of the immune response are deficient. The present work uses this model to analyze the interplay between cancer and the immune system, based on published literature. The work leans upon the etiology of alcohol and tobacco-related malignancies. The main conclusions are: triggers of specific “high Treg” immune reaction promote most non-hematologic cancers, whereas triggers of “low Treg” immune reaction promote lymphomas. The opposite is also true: triggers of specific “high Treg” immune reaction suppress lymphoma, whereas triggers of “low Treg” immune reaction suppress non-hematologic cancers. Both lymphoma and autoimmune diseases are “low Treg” conditions. For this reason, both are promoted by the same panel of “low Treg” bacteria and parasites and are inhibited by “high Treg” triggers. For example, alcohol consumption, a “high Treg” trigger, protects against lymphoma and autoimmune hypothyroidism. In addition, the same immune-modulatory drugs are effective in the treatment of both lymphoma and autoimmune diseases. Like other cancers, lymphoma transforms from a “low Treg” type at early stage of the disease into a “high Treg” type at advanced stages. However, lymphoma is distinguished from most other cancers by the length of time it dwells at an indolent “low Treg” state (many years) before lymphoma cells sensitivity to transforming growth factor-beta is impaired. This impairment stimulates the switch from “low Treg” into “high Treg” response and results in immune escape. The application of this analysis to the pharmacological activity of checkpoint inhibitors forecasts that checkpoint inhibitors would not be effective in low-grade, indolent lymphomas. As of now, checkpoint inhibitors are approved for the treatment of advanced lymphoma only.

Dataset Information

Potential effect of tumor-specific Treg-targeted antibodies in the treatment of human cancers: A bioinformatics analysis.

Publications

Potential effect of tumor-specific Treg-targeted antibodies in the treatment of human cancers: A bioinformatics analysis.

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