Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance.

Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues. The differential functions of heterogeneous stem cells and niches are important given the increasing clinical applications of stem-cell transplantation and immunotherapy. Whether hierarchical structures among stem cells at distinct niches exist and further control aspects of immune tolerance is unknown.

In vitro-irradiated cancer vaccine enhances anti-tumor efficacy of radiotherapy and PD-L1 blockade in a syngeneic murine breast cancer model.

Background And Purpose: Local radiotherapy (RT) exerts immunostimulatory effects by inducing immunogenic cell death. However, it remains unknown whether in vitro-irradiated tumor cells can elicit anti-tumor responses and enhance the efficacy of local RT and immune checkpoint inhibitors when injected in vivo.

Methods And Materials: We tested the "in vitro-irradiated cancer vaccine (ICV)", wherein tumor cells killed by varying doses of irradiation and their supernatants are intravenously injected.

Combination of local radiotherapy and anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) therapy augments PD-L1 blockade-mediated anti-tumor effects in murine breast cancer model.

Purpose: In this study, we investigated whether local radiotherapy (RT) and an anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) agonist could increase the efficacy of PD-L1 blockade.

Methods And Materials: We analyzed a breast cancer dataset from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) to determine the role of GITR in breast cancer. We used the 4T1 murine TNBC model (primary and secondary tumors) to investigate the efficacy of PD-L1 blockade, local RT, anti-GITR agonist, and their combinations.

BRD4 Inhibition Enhances the Antitumor Effects of Radiation Therapy in a Murine Breast Cancer Model.

Bromodomain-containing protein 4 (BRD4) is an intracellular protein that regulates expression of various cellular functions. This study investigated whether BRD4 inhibition can alter the immunomodulatory and antitumor effects of radiation therapy (RT). A murine breast cancer cell line was implanted into BALB/c mice.

Combination of OX40 Co-Stimulation, Radiotherapy, and PD-1 Inhibition in a Syngeneic Murine Triple-Negative Breast Cancer Model.

Immune checkpoint inhibitors have been successful in a wide range of tumor types but still have limited efficacy in immunologically cold tumors, such as breast cancers. We hypothesized that the combination of agonistic anti-OX40 (α-OX40) co-stimulation, PD-1 blockade, and radiotherapy would improve the therapeutic efficacy of the immune checkpoint blockade in a syngeneic murine triple-negative breast cancer model. Murine triple-negative breast cancer cells (4T1) were grown in immune-competent BALB/c mice, and tumors were irradiated with 24 Gy in three fractions.

PI3Kγδ inhibitor plus radiation enhances the antitumour immune effect of PD-1 blockade in syngenic murine breast cancer and humanised patient-derived xenograft model.

Introduction: We hypothesised that the combined use of radiation therapy and a phosphoinositide 3-kinaseγδ inhibitor to reduce immune suppression would enhance the efficacy of an immune checkpoint inhibitor.

Methods: Murine breast cancer cells (4T1) were grown in both immune-competent and -deficient BALB/c mice, and tumours were irradiated by 3 fractions of 24 Gy. A PD-1 blockade and a phosphoinositide 3-kinase (PI3K)γδ inhibitor were then administered every other day for 2 weeks.

PI3Kαδ Inhibitor Combined With Radiation Enhances the Antitumor Immune Effect of Anti-PD1 in a Syngeneic Murine Triple-Negative Breast Cancer Model.

Purpose: The poor response of breast cancer to immune checkpoint blockade might result from low immunogenicity and the immune-suppressive tumor microenvironment. We hypothesized that in situ tumor vaccination via radiation therapy (RT) and suppression of immune tolerance via phosphoinositide 3-kinase δ (PI3Kδ) inhibition would enhance the efficacy of immune checkpoint blockade.

Methods And Materials: 4T1 murine breast cancer cells were grown in both immune-competent and -deficient BALB/c mice, and tumors were irradiated with 24 Gy in 3 fractions.