Complete rejection of large established breast cancer by local immunochemotherapy with T cell activation against neoantigens

Effector CD8+ T cell activation and its cytotoxic function are positively correlated with improved survival in breast cancer. tRNA-derived fragments (tRFs) have recently been found to be involved in gene regulation in cancer progression. However, it is unclear how interactions between expression of tRFs and T cell activation affect breast cancer patient survival. We used Kaplan–Meier survival and multivariate Cox regression models to evaluate the effect of interactions between expression of tRFs and T cell activation on survival in 1081 breast cancer patients. Spearman correlation analysis and weighted gene co-expression network analysis were conducted to identify genes and pathways that were associated with tRFs. tRFdb-5024a, 5P_tRNA-Leu-CAA-4-1, and ts-49 were positively associated with overall survival, while ts-34 and ts-58 were negatively associated with overall survival. Significant interactions were detected between T cell activation and ts-34 and ts-49. In the T cell exhaustion group, patients with a low level of ts-34 or a high level of ts-49 showed improved survival. In contrast, there was no significant difference in the activation group. Breast cancer related pathways were identified for the five tRFs. In conclusion, the identified five tRFs associated with overall survival may serve as therapeutic targets and improve immunotherapy in breast cancer.

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Focused ultrasound therapy combined with pembrolizumab in metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.tps19 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. TPS19-TPS19

Author(s):

Patrick Michael Dillon ◽

Bethany J Horton ◽

Timothy Bullock ◽

Christiana Brenin ◽

David R. Brenin

Keyword(s):

Breast Cancer ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Focused Ultrasound ◽

Metastatic Breast ◽

High Energy ◽

Antitumor Effects ◽

Ablative Therapy ◽

Metastatic Setting

TPS19 Background: Focused ultrasound (FUS) is an ablative therapy which can heat tumors rapidly to cell damaging temperatures and simultaneously perturb the microenvironment, the microvasculature, and the lymphatics. At typical energy levels, FUS can induce controlled apoptotic cell death rather than liquefactive necrosis. FUS does not involve radiation. FUS is a partially ablative therapy using high energy ultrasound waves to induce heat shock proteins, cytokine release and cellular mediated mechanisms resulting in T cell activation and recognition of tumor antigens. FUS has been demonstrated to be an effective method for inducing tumor antigen exposure and presentation to dendritic cells, thus acting as an auto-vaccine. Pembrolizumab (PBZ) is a PD-1 targeted antibody used in multiple solid tumors to augment T cell activation. It is hypothesized that the combination of these two modalities will result in T cell infiltration into breast tumors as well as systemic immune responses. Methods: In this pilot study, we will examine PBZ therapy in combination with FUS to assess for immune stimulation and antitumor effects at local ablation sites, distant non-treated sites and in the blood. Biopsy before and after treatments will examine the tissue in the peripheral zone of ablation as well as at distant metastatic sites for CD8 and CD4 T cells, MDSC’s, T-regulatory cells and cytokine responses. Twelve patients will be randomized to receive either PBZ 14 days before or 7 days after a single time FUS partial tumor ablation on day 15. Biopsies will be on days 1, 22 and 64 and tumor imaging will be every 12 weeks. Patients must have metastatic or unresectable breast cancer, adequate organ function, and prior therapy in the metastatic setting. They must also have a tumor in the breast or axilla amenable to FUS and biopsy. Clinical trial information: NCT03237572.

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BRCA1 mRNA expression modifies the effect of T cell activation score on patient survival in breast cancer

BMC Cancer ◽

10.1186/s12885-019-5595-3 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 5

Author(s):

Lingeng Lu ◽

Huatian Huang ◽

Jing Zhou ◽

Wenxue Ma ◽

Sean Mackay ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Mrna Expression ◽

T Cell Activation ◽

Cell Activation ◽

Patient Survival ◽

Brca1 Mrna

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CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation

Journal for ImmunoTherapy of Cancer ◽

10.1186/s40425-018-0347-5 ◽

2018 ◽

Vol 6 (1) ◽

Cited By ~ 30

Author(s):

Pradip Bajgain ◽

Supannikar Tawinwung ◽

Lindsey D’Elia ◽

Sujita Sukumaran ◽

Norihiro Watanabe ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Cell Therapy ◽

T Cell Activation ◽

Cell Activation ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

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Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

OncoImmunology ◽

10.1080/2162402x.2014.995562 ◽

2015 ◽

Vol 4 (3) ◽

pp. e995562 ◽

Cited By ~ 18

Author(s):

Simon Gebremeskel ◽

Daniel R. Clattenburg ◽

Drew Slauenwhite ◽

Lynnea Lobert ◽

Brent Johnston

Keyword(s):

Breast Cancer ◽

T Cell ◽

Natural Killer ◽

T Cell Activation ◽

Cell Activation ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Natural Killer T Cell ◽

Killer T Cell ◽

Natural Killer T

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Transcriptomic Profiles of CD47 in Breast Tumors Predict Outcome and Are Associated with Immune Activation

International Journal of Molecular Sciences ◽

10.3390/ijms22083836 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3836

Author(s):

María del Mar Noblejas-López ◽

Mariona Baliu-Piqué ◽

Cristina Nieto-Jiménez ◽

Francisco J. Cimas ◽

Esther C. Morafraile ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Breast Tumors ◽

Gene Signature ◽

Immune Gene ◽

Cancer Subtypes ◽

Immune Signature ◽

Her2 Breast Cancer

Targeting the innate immune system has attracted attention with the development of anti- CD47 antibodies. Anti-CD47 antibodies block the inhibition of the phagocytic activity of macrophages caused by the up-regulation of CD47 on tumor cells. In this study, public genomic data was used to identify genes highly expressed in breast tumors with elevated CD47 expression and analyzed the association between the presence of tumor immune infiltrates and the expression of the selected genes. We found that 142 genes positively correlated with CD47, of which 83 predicted favorable and 32 detrimental relapse-free survival (RFS). From those associated with favorable RFS, we selected the genes with immunologic biological functions and defined a CD47-immune signature composed of PTPRC, HLA-E, TGFBR2, PTGER4, ETS1, and OPTN. In the basal-like and HER2+ breast cancer subtypes, the expression of the CD47-immune signature predicted favorable outcome, correlated with the presence of tumor immune infiltrates, and with gene expression signatures of T cell activation. Moreover, CD47 up-regulated genes associated with favorable survival correlated with pro-tumoral macrophages. In summary, we described a CD47-immune gene signature composed of 6 genes associated with favorable prognosis, T cell activation, and pro-tumoral macrophages in breast cancer tumors expressing high levels of CD47.

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cDC1 and interferons promote spontaneous CD4+ and CD8+ T cell protective responses to breast cancer

10.1101/2020.12.23.424092 ◽

2020 ◽

Author(s):

Raphaël Mattiuz ◽

Carine Brousse ◽

Marc Ambrosini ◽

Jean-Charles Cancel ◽

Gilles Bessou ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

T Cell Activation ◽

Cell Activation ◽

Tumor Antigens ◽

Breast Cancer Patients ◽

Ifn Γ ◽

Cancer Immunosurveillance

AbstractHere we show that efficient breast cancer immunosurveillance relies on cDC1, conventional CD4+ T cells, CD8+ cytotoxic T lymphocytes (CTL) and later NK/NK T cells. For this process, cDC1 were required constitutively, but especially during the T cell priming phase. In the tumor microenvironment, cDC1 interacted physically and jointly with both CD4+ T cells and tumorspecific CD8+ T cells. We found that interferon (IFN) responses were necessary for the rejection of breast cancer, including cDC1-intrinsic signaling by IFN-γ and STAT1. Surprisingly, cell-intrinsic IFN-I signaling in cDC1 was not required. cDC1 and IFNs shaped the tumor immune landscape, notably by promoting CD4+ and CD8+ T cell infiltration, terminal differentiation and effector functions. XCR1, CXCL9, IL-12 and IL-15 were individually dispensable for breast cancer immunosurveillance. Consistent with our experimental results in mice, high expression in the tumor microenvironment of genes specific to cDC1, CTL, helper T cells or interferon responses are associated with a better prognosis in human breast cancer patients. Our results show that immune control of breast cancer depends on cDC1 and IFNs as previously reported for immunogenic melanoma or fibrosarcoma tumor models, but that the underlying mechanism differ. Revisiting cDC1 functions in the context of spontaneous immunity to cancer should help defining new ways to mobilize cDC1 functions to improve already existing immunotherapies for the benefits of patients.SynopsisType 1 conventional dendritic cells cross-present tumor antigens to CD8+ T cells. Understanding the regulation of their antitumor functions is important. Cell-intrinsic STAT1/IFN-γ signaling licenses them for efficient CD4+ and CD8+ T cell activation during breast cancer immunosurveillance.

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