The Multifaceted Role of Regulatory T Cells in Breast Cancer

The microenvironment of breast cancer hosts a dynamic cross talk between diverse players of the immune system. While cytotoxic immune cells are equipped to control tumor growth and metastasis, tumor-corrupted immunosuppressive immune cells strive to impair effective immunity and promote tumor progression. Of these, regulatory T cells (Tregs), the gatekeepers of immune homeostasis, emerge as multifaceted players involved in breast cancer. Intriguingly, clinical observations suggest that blood and intratumoral Tregs can have strong prognostic value, dictated by breast cancer subtype. Accordingly, emerging preclinical evidence shows that Tregs occupy a central role in breast cancer initiation and progression and provide critical support to metastasis formation. Here, Tregs are not only important for immune escape but also promote tumor progression independent of their immune regulatory capacity. Combining insights into Treg biology with advances made across the rapidly growing field of immuno-oncology is expected to set the stage for the design of more effective immunotherapy strategies. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Breast cancer cell–derived IL-35 promotes tumor progression via induction of IL-35-producing induced regulatory T cells

Carcinogenesis ◽

10.1093/carcin/bgy136 ◽

2018 ◽

Vol 39 (12) ◽

pp. 1488-1496 ◽

Cited By ~ 13

Author(s):

Shengnan Hao ◽

Xi Chen ◽

Fang Wang ◽

Qianqian Shao ◽

Jia Liu ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Tumor Progression ◽

Cancer Cell ◽

Breast Cancer Cell

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Immunometabolism in the Tumor Microenvironment

Annual Review of Cancer Biology ◽

10.1146/annurev-cancerbio-030518-055817 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Dominic G. Roy ◽

Irem Kaymak ◽

Kelsey S. Williams ◽

Eric H. Ma ◽

Russell G. Jones

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Cancer Biology ◽

Antitumor Immunity ◽

Immune Cell ◽

Metabolic Reprogramming ◽

Proper Function ◽

Annual Review ◽

Publication Date ◽

And Function

Advances in immunotherapy have underscored the importance of antitumor immune responses in controlling cancer. However, the tumor microenvironment (TME) imposes several obstacles to the proper function of immune cells, including a metabolically challenging and immunosuppressive microenvironment. The increased metabolic activity of tumor cells can lead to the depletion of key nutrients required by immune cells and the accumulation of byproducts that hamper antitumor immunity. Furthermore, the presence of suppressive immune cells, such as regulatory T cells and myeloid-derived suppressor cells, and the expression of immune inhibitory receptors can negatively impact immune cell metabolism and function. This review summarizes the metabolic reprogramming that is characteristic of various immune cell subsets, discusses how the metabolism and function of immune cells is shaped by the TME, and highlights how therapeutic interventions aimed at improving the metabolic fitness of immune cells and alleviating the metabolic constraints in the TME can boost antitumor immunity. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8+ T cell exclusion

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01786-6 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Wenli Fang ◽

Ting Zhou ◽

He Shi ◽

Mengli Yao ◽

Dian Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Flow Cytometry ◽

T Cells ◽

Western Blot ◽

Tumor Immunity ◽

Immune Cells ◽

Immune Escape ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Programmed Death

Abstract Background Progranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. Here, we studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism. Methods The changes of macrophage phenotypes after PGRN treatment were detected by western blot, quantitative polymerase chain reaction (PCR) and flow cytometry. Western blot was used to study the signal molecular mechanism of PGRN regulating this process. The number and localization of immune cells in Wild-type (WT) and PGRN−/− breast cancer tissues were analyzed by immunohistochemical staining and immunofluorescence techniques. The activation and proliferation of CD8+ T cells were measured by flow cytometry. Results After being treated with PGRN, the expressions of M2 markers and programmed death ligand 1 (PD-L1) on macrophages increased significantly. Signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitor Stattic significantly inhibited the expression of PD-L1 and M2 related markers induced by PGRN. In WT group, CD8 were co-localized with macrophages and PD-L1, but not tumor cells. The number of immune cells in PGRN−/− breast cancer tissue increased, and their infiltration into tumor parenchyma was also enhanced. Moreover, in the co-culture system, WT peritoneal macrophages not only reduced the ratio of activated CD8+ T cells but also reduced the proportion of proliferating CD8+ T cells. The addition of programmed death receptor 1 (PD-1) and PD-L1 neutralizing antibodies effectively reversed this effect and restored the immune function of CD8+ T cells. Conclusion These results demonstrate that PGRN promotes M2 polarization and PD-L1 expression by activating the STAT3 signaling pathway. Furthermore, through PD-1/PD-L1 interaction, PGRN can promote the breast tumor immune escape. Our research may provide new ideas and targets for clinical breast cancer immunotherapy.

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Data-Driven Mathematical Model of Osteosarcoma

Cancers ◽

10.3390/cancers13102367 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2367

Author(s):

Trang Le ◽

Sumeyye Su ◽

Arkadz Kirshtein ◽

Leili Shahriyari

Keyword(s):

Mathematical Model ◽

T Cells ◽

Immune System ◽

Regulatory T Cells ◽

Tumor Progression ◽

Immune Cells ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Decay Rates ◽

Data Driven

As the immune system has a significant role in tumor progression, in this paper, we develop a data-driven mathematical model to study the interactions between immune cells and the osteosarcoma microenvironment. Osteosarcoma tumors are divided into three clusters based on their relative abundance of immune cells as estimated from their gene expression profiles. We then analyze the tumor progression and effects of the immune system on cancer growth in each cluster. Cluster 3, which had approximately the same number of naive and M2 macrophages, had the slowest tumor growth, and cluster 2, with the highest population of naive macrophages, had the highest cancer population at the steady states. We also found that the fastest growth of cancer occurred when the anti-tumor immune cells and cytokines, including dendritic cells, helper T cells, cytotoxic cells, and IFN-γ, switched from increasing to decreasing, while the dynamics of regulatory T cells switched from decreasing to increasing. Importantly, the most impactful immune parameters on the number of cancer and total cells were the activation and decay rates of the macrophages and regulatory T cells for all clusters. This work presents the first osteosarcoma progression model, which can be later extended to investigate the effectiveness of various osteosarcoma treatments.

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Progranulin Induces Immune Escape in Breast Cancer Via Up-Regulating PD-L1 Expression on TAMS and Promoting CD8+T cell Exclusion

10.21203/rs.3.rs-79474/v1 ◽

2020 ◽

Author(s):

Wenli Fang ◽

Ting Zhou ◽

He Shi ◽

Mengli Yao ◽

Dian Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Flow Cytometry ◽

T Cells ◽

Western Blot ◽

Molecular Mechanism ◽

Tumor Immunity ◽

Immune Cells ◽

Immune Escape ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway

Abstract Background: Progranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. Here, we studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism.Methods: The changes of macrophage phenotypes after PGRN treatment were detected by western blot, quantitative PCR and flow cytometry. Western blot was used to study the signal molecular mechanism of PGRN regulating this process. The number and localization of immune cells in WT and PGRN-/- breast cancer tissues were analyzed by immunohistochemical staining and immunofluorescence techniques. The activation and proliferation of CD8+ T cells were measured by flow cytometry.Results: After being treated with PGRN, the expressions of M2 markers and PD-L1 on macrophages increased. STAT3 signaling pathway inhibitor Stattic could significantly inhibit PD-L1 expression and M2 related markers induced by PGRN. In WT group, CD8 were co-localized with macrophages and PD-L1, but not tumor cells. The number of immune cells in PGRN-/- breast cancer tissue increased, and the infiltration into tumor parenchyma also increased. Moreover, in the co-culture system, WT peritoneal macrophages not only reduced the ratio of activated CD8+T cells but also reduced the proportion of proliferating CD8+T cells. The addition of PD-1 and PD-L1 neutralizing antibodies could effectively reverse this effect and restore the immune function of CD8+T cells.Conclusion: The results show that PGRN can promote M2 polarization and PD-L1 expression by activating the STAT3 signaling pathway. Furthermore, through PD-1/PD-L1 interaction, PGRN can promote the breast tumor immune escape. Our research may provide new ideas and targets for clinical breast cancer immunotherapy.

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Molecular Heterogeneity and Evolution in Breast Cancer

Annual Review of Cancer Biology ◽

10.1146/annurev-cancerbio-060220-014137 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Jennifer L. Caswell-Jin ◽

Carina Lorenz ◽

Christina Curtis

Keyword(s):

Breast Cancer ◽

Cancer Biology ◽

Expression Profiles ◽

Genetic Alterations ◽

Intratumor Heterogeneity ◽

Annual Review ◽

Publication Date ◽

Molecular Heterogeneity ◽

Tumor Subtypes ◽

Current State

Breast cancer comprises a heterogeneous group of tumor subtypes, whether defined by immunohistochemistry of key proteins, RNA expression profiles, or genetic alterations, and each of these subtypes may benefit from a distinct treatment approach. However, there can be striking heterogeneity within tumors, which may pose challenges to the development of personalized approaches to therapy. Intratumor heterogeneity can be divided into three main categories: genetic, phenotypic, and microenvironmental. Here, we review technologies to interrogate these three categories of heterogeneity in patient samples, as well as the current state of understanding of these categories in breast cancer, from cell to cell, across different regions of the same tumor mass, across treatment, and across metastasis. Efforts to characterize tumor heterogeneity longitudinally will be crucial to the development of personalized oncology for breast cancer. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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A Perspective of Immunotherapy for Breast Cancer: Lessons Learned and Forward Directions for All Cancers

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s29425 ◽

2015 ◽

Vol 9s2 ◽

pp. BCBCR.S29425 ◽

Cited By ~ 1

Author(s):

George R. Nahas ◽

Nykia D. Walker ◽

Margarette Bryan ◽

Pranela Rameshwar

Keyword(s):

Breast Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Immune Cells ◽

Mononuclear Cells ◽

Ex Vivo ◽

Lessons Learned ◽

Inflammatory Microenvironment ◽

Tumor Protection

Immunotherapy for cancer has been a focus 50 years ago. At the time, this treatment was developed prior to cloning of the cytokines, no knowledge of regulatory T-cells, and very little information that mesenchymal stem cells (MSCs) (originally colony forming unit-fibroblasts [CFU-F]) could be licensed by the inflammatory microenvironment to suppress an immune response. Given the information available at that time, mononuclear cells from the peripheral blood were activated ex vivo and then replaced in the patients with tumor. The intent was to harness these activated immune cells to target the cancer cells. These studies did not lead to long-term responses because the activated cells when reinfused into the patients were an advantage to the resident MSCs, which can home the tumor and then become suppressive in the presence of the immune cells. The immune suppression caused by MSCs would also expand regulatory T-cells, resulting instead in tumor protection. As time progressed, these different fields converged into a new approach to use immunotherapy for cancer. This article discusses these approaches and also reviews chimeric antigen receptor in the context of future treatments for solid tumors, including breast cancer.

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Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors

10.1101/525071 ◽

2019 ◽

Cited By ~ 3

Author(s):

Li Zhu ◽

Jessica L. Narloch ◽

Sayali Onkar ◽

Marion Joy ◽

Catherine Luedke ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Immune Cells ◽

Cancer Metastasis ◽

Immune Cell ◽

Immune Escape ◽

Metastatic Breast ◽

Exome Capture ◽

Sequencing Data ◽

Primary Tumors

AbstractThe interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TIL) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs have a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain (BRM) METs by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study.

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Effect of Equipotent Doses of Propofol versus Sevoflurane Anesthesia on Regulatory T Cells after Breast Cancer Surgery

Anesthesiology ◽

10.1097/aln.0000000000002382 ◽

2018 ◽

Vol 129 (5) ◽

pp. 921-931 ◽

Cited By ~ 8

Author(s):

Chung-Sik Oh ◽

Jaemoon Lee ◽

Tae-Gyoon Yoon ◽

Eun-Hye Seo ◽

Hyun-Jun Park ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Immune Cells ◽

Cytotoxic T Cells ◽

Cancer Surgery ◽

Helper T Cells ◽

Breast Cancer Surgery ◽

Cluster Of Differentiation

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Clusters of differentiation 39 and 73, enzymes expressed on the surface of regulatory T cells, promote cancer recurrence and metastasis by suppressing immune cells. The authors hypothesized that propofol is less immunosuppressive than volatile anesthetics. The objective of this randomized trial was to compare the changes in cluster of differentiation 39 and 73 expression on regulatory T cells between propofol- and sevoflurane-based anesthesia during breast cancer surgery. Methods A total of 201 patients having breast cancer surgery were randomly assigned and analyzed (n = 99 for propofol, n = 102 for sevoflurane). Blood samples were obtained immediately before anesthesia induction and 1 and 24 h postoperatively. The frequency of cluster of differentiation 39 and 73 expression on circulating regulatory T cells (primary outcome) and the frequency of circulating type 1 and type 17 helper T cells, natural killer cells, and cytotoxic T cells were investigated. Serum cytokines and the neutrophil-to-lymphocyte ratio were also evaluated. Results Changes in cluster of differentiation 39 and 73 expression on regulatory T cells over time did not differ with propofol and sevoflurane groups (difference [95% confidence interval]: 0.01 [−2.04 to 2.06], P = 0.995 for cluster of differentiation 39; −0.93 [−3.12 to 1.26], P = 0.403 for cluster of differentiation 73). There were no intergroup differences in type 1, type 17 helper T cells, natural killer cells, cytotoxic T cells, cytokines, or the neutrophil-to-lymphocyte ratio. Conclusions Changes in immune cells were similar with propofol and sevoflurane during breast cancer surgery. The effect of anesthetics on the perioperative immune activity may be minimal during cancer surgery.

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Mathematical Modelling of the Inhibitory Role of Regulatory T Cells in Tumor Immune Response

Complexity ◽

10.1155/2020/4834165 ◽

2020 ◽

Vol 2020 ◽

pp. 1-21

Author(s):

Zhongtao Yang ◽

Cuihong Yang ◽

Yueping Dong ◽

Yasuhiro Takeuchi

Keyword(s):

T Cells ◽

Immune System ◽

Regulatory T Cells ◽

Immune Cells ◽

Immune Escape ◽

Critical Value ◽

Inhibitory Effect ◽

Tumor Escape ◽

Tumor Immune Escape ◽

Stimulation Rate

The immune system against tumors acts through a complex dynamical process showing a dual role. On the one hand, the immune system can activate some immune cells to kill tumor cells (TCs), such as cytotoxic T lymphocytes (CTLs) and natural killer cells (NKs), but on the other hand, more evidence shows that some immune cells can help tumor escape, such as regulatory T cells (Tregs). In this paper, we propose a tumor immune interaction model based on Tregs-mediated tumor immune escape mechanism. When helper T cells’ (HTCs) stimulation rate by the presence of identified tumor antigens is below critical value, the coexistence (tumor and immune) equilibrium is always stable in its existence region. When HTCs stimulation rate is higher than the critical value, the inhibition rate of effector cells (ECs) by Tregs can destabilize the coexistence equilibrium and cause Hopf bifurcations and produce a limit cycle. This model shows that Tregs might play a crucial role in triggering the tumor immune escape. Furthermore, we introduce the adoptive cellular immunotherapy (ACI) and monoclonal antibody immunotherapy (MAI) as the treatment to boost the immune system to fight against tumors. The numerical results show that ACI can control TCs more, while MAI can delay the inhibitory effect of Tregs on ECs. The result also shows that the combination of both immunotherapies can control TCs and reduce the inhibitory effect of Tregs better than a single immunotherapy can control.

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