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Tumor-associated macrophages promote intratumoral conversion of conventional CD4⁺ T cells into regulatory T cells via PD-1 signalling.

ABSTRACT: While regulatory T cells (T_regs) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of T_regs by promoting the conversion of conventional CD4⁺ T cells (T_convs) into T_regs. Mechanistically, two processes were identified that independently contribute to this process. While TAM-derived TGF-β directly promotes the conversion of CD4⁺ T_convs into T_regs in vitro, we additionally show that TAMs enhance PD-1 expression on CD4⁺ T cells. This indirectly contributes to the intratumoral accumulation of T_regs, as loss of PD-1 on CD4⁺ T_convs abrogates intratumoral conversion of adoptively transferred CD4⁺ T_convs into T_regs. Combined, this study provides insights into the complex immune cell crosstalk between CD4⁺ T cells and TAMs in the tumor microenvironment of breast cancer, and further highlights that therapeutic exploitation of macrophages may be an attractive immune intervention to limit the accumulation of T_regs in breast tumors.

SUBMITTER: Kos K

PROVIDER: S-EPMC9037432 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Tumor-associated macrophages promote intratumoral conversion of conventional CD4+ T cells into regulatory T cells via PD-1 signalling.

Kos Kevin K Salvagno Camilla C Wellenstein Max D MD Aslam Muhammad A MA Meijer Denize A DA Hau Cheei-Sing CS Vrijland Kim K Kaldenbach Daphne D Raeven Elisabeth A M EAM Schmittnaegel Martina M Ries Carola H CH de Visser Karin E KE

Oncoimmunology 20220415 1

While regulatory T cells (Tregs) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of Tregs by promoting the conversion of conventional CD4+ T cells (Tconvs) into Tregs. Mechani ...[more]

PMID: 35481289

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Project description:The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly. Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.

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Tumor-associated macrophages promote intratumoral conversion of conventional CD4⁺ T cells into regulatory T cells via PD-1 signalling.

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Tumor-associated macrophages promote intratumoral conversion of conventional CD4<sup>+</sup> T cells into regulatory T cells via PD-1 signalling.

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Tumor-associated macrophages promote intratumoral conversion of conventional CD4+ T cells into regulatory T cells via PD-1 signalling.

Publications

Tumor-associated macrophages promote intratumoral conversion of conventional CD4&lt;sup&gt;+&lt;/sup&gt; T cells into regulatory T cells via PD-1 signalling.

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OmicsDI is part of the ELIXIR infrastructure

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Tumor-associated macrophages promote intratumoral conversion of conventional CD4⁺ T cells into regulatory T cells via PD-1 signalling.

Tumor-associated macrophages promote intratumoral conversion of conventional CD4<sup>+</sup> T cells into regulatory T cells via PD-1 signalling.