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Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction.

ABSTRACT: Tregs control various functions of effector T cells; however, where and how Tregs exert their immunomodulatory effects remain poorly understood. Here we developed a murine model of adoptive T cell therapy and found that Tregs induce a dysfunctional state in tumor-infiltrating CTLs that resembles T cell exhaustion and is characterized by low expression of effector cytokines, inefficient cytotoxic granule release, and coexpression of coinhibitory receptors PD-1 and TIM-3. Induction of CTL dysfunction was an active process, requiring local TCR signals in tumor tissue. Tregs infiltrated tumors only subsequent to Ag-dependent activation and expansion in tumor-draining LNs; however, Tregs also required local Ag reencounter within tumor tissue to induce CTL dysfunction and prevent tumor rejection. Multiphoton intravital microscopy revealed that in contrast to CTLs, Tregs only rarely and briefly interrupted their migration in tumor tissue in an Ag-dependent manner and formed unstable tethering-interactions with CD11c+ APCs, coinciding with a marked reduction of CD80 and CD86 on APCs. Activation of CTLs by Treg-conditioned CD80/86lo DCs promoted enhanced expression of both TIM-3 and PD-1. Based on these data, we propose that Tregs locally change the costimulatory landscape in tumor tissue through transient, Ag-dependent interactions with APCs, thus inducing CTL dysfunction by altering the balance of costimulatory and coinhibitory signals these cells receive.

SUBMITTER: Bauer CA

PROVIDER: S-EPMC4089459 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction.

Bauer Christian A CA Kim Edward Y EY Marangoni Francesco F Carrizosa Esteban E Claudio Natalie M NM Mempel Thorsten R TR

The Journal of clinical investigation 20140508 6

Tregs control various functions of effector T cells; however, where and how Tregs exert their immunomodulatory effects remain poorly understood. Here we developed a murine model of adoptive T cell therapy and found that Tregs induce a dysfunctional state in tumor-infiltrating CTLs that resembles T cell exhaustion and is characterized by low expression of effector cytokines, inefficient cytotoxic granule release, and coexpression of coinhibitory receptors PD-1 and TIM-3. Induction of CTL dysfunct ...[more]

PMID: 24812664

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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

Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction.

Publications

Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction.

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