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Parity improves anti-tumor immunity in breast cancer patients.

ABSTRACT: Compared to nulliparous women, parous women have an up to 50% lower lifetime risk of developing breast cancer. An endogenous mechanism to prevent the development of cancer is the destruction of tumor cells by T cells that recognize tumor-associated antigens (TAA). Since a number of TAA are also highly present in the breast and placenta of pregnant women, we investigated the induction and characteristics of spontaneous T cell responses against TAA during pregnancy. To this end, we collected peripheral blood from healthy nulliparous, primigravid and parous women, as well as from breast cancer patients. IFN-? ELISpot assays were performed to measure the intensity and specificity of T cell responses against 11 different TAA. The impact of TAA-specific Treg cells on anti-TAA responses was assessed by performing the assay before and after depletion of CD4+CD25+ T cells. The antigenic specificities of these Treg cells were analyzed by the Treg specificity assay. Furthermore, we conducted flow cytometric analyses to determine the memory phenotype and cytokine secretion profile of TAA-specific T cells. Our results demonstrate that pregnancy induces functional and long-lived memory and effector T cells that react against multiple TAA. These persist for many decades in parous females, but are not found in age-matched females without children. We also detected TAA-specific Treg cells, which suppressed strong effector T cell responses after delivery. Nulliparous breast cancer patients displayed median TAA-specific effector T cell responses to be decreased threefold compared to parous patients, which could be restored in vitro after depletion of Treg cells.

SUBMITTER: Krause AL

PROVIDER: S-EPMC5739613 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Parity improves anti-tumor immunity in breast cancer patients.

Krause Anna-Lena AL Schuetz Florian F Boudewijns Marc M Pritsch Maria M Wallwiener Markus M Golatta Michael M Rom Joachim J Heil Joerg J Sohn Christof C Schneeweiss Andreas A Beckhove Philipp P Domschke Christoph C

Oncotarget 20170908 62

Compared to nulliparous women, parous women have an up to 50% lower lifetime risk of developing breast cancer. An endogenous mechanism to prevent the development of cancer is the destruction of tumor cells by T cells that recognize tumor-associated antigens (TAA). Since a number of TAA are also highly present in the breast and placenta of pregnant women, we investigated the induction and characteristics of spontaneous T cell responses against TAA during pregnancy. To this end, we collected perip ...[more]

PMID: 29285226

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Project description:Background Metastatic breast cancer (mBC) is a heterogeneous disease with varying responses to treatments and clinical outcomes, still requiring the identification of reliable predictive biomarkers. In this context, liquid biopsy has emerged as a powerful tool to assess in real-time the evolving landscape of cancer, which is both orchestrated by the metastatic process and immune-surveillance mechanisms. Thus, we investigated circulating tumor cells (CTCs) coupled with peripheral T-cell immunity to uncover their potential clinical relevance in mBC. Methods A cohort of 20 mBC patients was evaluated, before and one month after starting therapy, through the following liquid biopsy approaches: CTCs enumerated by a metabolism-based assay, T-cell responses against tumor-associated antigens (TAA) characterized by interferon-γ enzyme-linked immunosorbent spot (ELISpot), and the T-cell receptor (TCR) repertoire investigated by a targeted next-generation sequencing technique. TCR repertoire features were characterized by the Morisita’s overlap and the Productive Simpson Clonality indexes, and the TCR richness. Differences between groups were calculated by Fisher’s, Mann-Whitney or Kruskal-Wallis test, as appropriate. Prognostic data analysis was estimated by Kaplan-Meier method. Results Stratifying patients for their prognostic level of 6 CTCs before therapy, TAA specific T-cell responses were detected only in patients with a low CTC level. By analyzing the TCR repertoire, the highest TCR clonality was observed in the case of CTCs under the cut-off and a positive ELISpot response (p=0.03). Whereas, at follow-up, patients showing a good clinical response coupled with a low number of CTCs were characterized by the most elevated TCR clonality (p<0.05). The detection of CTCs≥6 in at least one time-point was associated with a lower TCR clonality (p=0.02). Intriguingly, by combining overall survival analysis with TCR repertoire, we highlighted a potential prognostic role of the TCR clonality measured at follow-up (p=0.03). Conclusion These data, whether validated in a larger cohort of patients, suggest that the combined analysis of CTCs and circulating anti-tumor T-cell immunity could represent a valuable immune-oncological biomarker for the liquid biopsy field. The clinical application of this promising tool could improve the management of mBC patients, especially in the setting of immunotherapy, a rising approach for BC treatment requiring reliable predictive biomarkers.

Project description:Necroptosis is a form of regulated necrosis and is executed by MLKL when MLKL is engaged in triggering the rupture of cell plasma membrane. MLKL activation also leads to the protease, ADAMs-mediated ectodomain shedding of cell surface proteins of necroptotic cells. Tumor necroptosis often happens in advanced solid tumors, and blocking necroptosis by MLKL deletion in breast cancer dramatically reduces tumor metastasis. It has been suggested that tumor necroptosis affects tumor progression through modulating the tumor microenvironment. However, the exact mechanism by which tumor necroptosis promotes tumor metastasis remains elusive. Here, we report that the ectodomain shedding of cell surface proteins of necroptotic cells is critical for the promoting effect of tumor necroptosis in tumor metastasis through inhibiting the anti-tumor activity of T cells. We found that blocking tumor necroptosis by MLKL deletion led to the dramatic reduction of tumor metastasis and significantly elevated anti-tumor activity of tumor-infiltrating and peripheral blood T cells. Importantly, the increased anti-tumor activity of T cells is a key cause for the reduced metastasis as the depletion of CD8+ T cells completely restored the level of metastasis in the Mlkl KO mice. Interestingly, the levels of some soluble cell surface proteins including sE-cadherin that are known to promote metastasis are also dramatically reduced in MLKL null tumors/mice. Administration of ADAMs pan inhibitor reduces the levels of soluble cell surface proteins in WT tumors/mice and leads to the dramatic decrease in metastasis. Finally, we showed the sE-cadherin/KLRG1 inhibitory receptor is the major pathway for necroptosis-mediated suppression of the anti-tumor activity of T cells and the promotion of metastasis. Hence, our study reveals a novel mechanism of tumor necroptosis-mediated promotion of metastasis and suggests that tumor necroptosis and necroptosis-activated ADAMs are potential targets for controlling metastasis.

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Parity improves anti-tumor immunity in breast cancer patients.

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Parity improves anti-tumor immunity in breast cancer patients.

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