B Cells and T Follicular Helper Cells Mediate Response to Checkpoint Inhibitors in High Mutation Burden Mouse Models of Breast Cancer

This study identifies mechanisms mediating responses to immune checkpoint inhibitors using mouse models of triple-negative breast cancer. By creating new mammary tumor models, we find that tumor mutation burden and specific immune cells are associated with response. Further, we developed a rich resource of single-cell RNA-seq and bulk mRNA-seq data of immunotherapy-treated and non-treated tumors from sensitive and resistant murine models. Using this, we uncover that immune checkpoint therapy induces T follicular helper cell activation of B cells to facilitate the anti-tumor response in these models. We also show that B cell activation of T cells and the generation of antibody are key to immunotherapy response and propose a new biomarker for immune checkpoint therapy. In total, this work presents resources of new preclinical models of breast cancer with large mRNA-seq and single-cell RNA-seq datasets annotated for sensitivity to therapy and uncovers new components of response to immune checkpoint inhibitors.Graphical Abstract
Source: Cell - Category: Cytology Source Type: research

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AbstractThe poly-(ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib, have recently been approved for use in patients with metastatic breast cancer (BC) and germline BRCA 1 or 2 mutations due to improved progression-free survival compared to chemotherapy. An increasing number of clinical trials are evaluating the role of PARP inhibitors (PARPi) in BC, alone and in combination with other therapies (including immunotherapy), as well as in earlier stages of the disease. This review describes the unique mechanism of action of these drugs and puts into clinical context the results of pivotal clinical trials. We a...
Source: Drugs - Category: Drugs & Pharmacology Source Type: research
Immunotherapy, Ahead of Print.
Source: Immunotherapy - Category: Allergy & Immunology Authors: Source Type: research
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Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
Authors: Babaer D, Zheng M, Ivy MT, Zent R, Tiriveedhi V Abstract Previous phase I DNA-vaccine based clinical trials using Mammaglobin-A (Mam-A), a human breast tumor associated antigen (TAA), demonstrated that this agent was safe and efficient at treating patients with stage IV breast cancer. The long-term success of cancer vaccines is limited by the diminished expression of human leukocyte antigen (HLA) class I molecules in the tumor microenvironment. The current study assessed the impact of various selenocompounds on the expression of HLA class I molecules in THP-1 cells, an apparent proficient antigen that pres...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
Authors: Han RH, Dunn GP, Chheda MG, Kim AH Abstract Metastases from melanoma, lung and breast cancer are among the most common causes of intracranial malignancy. Standard of care for brain metastases include a combination of surgical resection, stereotactic radiosurgery, and whole-brain radiation. However, evidence continues to accumulate regarding the efficacy of molecularly-targeted systemic treatments and immunotherapy. For non-small cell lung cancer (NSCLC), numerous clinical trials have demonstrated intracranial activity for inhibitors of EGFR and ALK. Patients with melanoma brain metastases may benefit from ...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
In this study, we postulated that eIF4A could be a vulnerable node in BCSCs. In order to test this, we generated a paclitaxel-resistant TNBC cell line which demonstrated an elevated level of eIF4A along with increased levels of cancer stemness markers (ALDH activity and CD44), pluripotency transcription factors (SOX2, OCT4, and NANOG) and drug transporters (ABCB1, ABCG2, and ABCC1). Furthermore, genetic ablation of eIF4A resulted in reduced expression of ALDH1A1, pluripotency transcription factors and drug transporters. This pointed out that eIF4A is likely associated with selected set of proteins that are critical to BCSC...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
AbstractPurpose of ReviewImmune checkpoint inhibitors (ICIs) are an emerging therapy in breast cancer, but not all patients will have benefit with these medications. It has been proposed that certain gut microbes may play a role in protecting the host against inappropriate inflammation and modulating the immune response. Here, we review the current evidence on the association of the gut microbiome, antitumor immunity, and response to immunotherapy and discuss open questions, ongoing trials, and future directions for modulating the gut microbiome as part of breast cancer treatment.Recent FindingsSeveral groups have showed t...
Source: Current Breast Cancer Reports - Category: Cancer & Oncology Source Type: research
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Source: Aging - Category: Biomedical Science Authors: Tags: Aging (Albany NY) Source Type: research
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Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
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Source: Cancer Treatment Reviews - Category: Cancer & Oncology Authors: Tags: Tumour Review Source Type: research
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