Chemotherapy Coupled to Macrophage Inhibition Induces T-cell and B-cell Infiltration and Durable Regression in Triple-Negative Breast Cancer

Immunosuppressive elements within the tumor microenvironment, such as tumor-associated macrophages (TAM), can present a barrier to successful antitumor responses by cytolytic T cells. Here we employed preclinical syngeneic p53 null mouse models of triple-negative breast cancer (TNBC) to develop a treatment regimen that harnessed the immunostimulatory effects of low-dose cyclophosphamide coupled with the pharmacologic inhibition of TAMs using either a small-molecule CSF1R inhibitor or an anti-CSF1R antibody. This therapeutic combination was effective in treating several highly aggressive TNBC murine mammary tumor and lung metastasis models. Single-cell RNA sequencing characterized tumor-infiltrating lymphocytes including Th cells and antigen-presenting B cells that were highly enriched in responders to combination therapy. In one model that exhibited long-term posttreatment tumor regression, high-dimensional imaging techniques identified the close spatial localization of B220þ/CD86þ-activated B cells and CD4þ T cells in tertiary lymphoid structures that were present up to 6 weeks posttreatment. The transcriptional and metabolic heterogeneity of TAMs was also characterized in two closely related claudin-low/mesenchymal subtype tumor models with differential treatment responses. A murine TAM signature derived from the T12 model was highly conserved in human claudin-low breast cancers, and high expression of the TAM signature correlated with reduced overall survival in patients with breast cancer. This TAM signature may help identify human patients with claudin-low breast cancer that will benefit from the combination of cyclophosphamide and anti-CSF1R therapy. These studies illustrate the complexity of the tumor immune microenvironment and highlight different immune responses that result from rational immunotherapy combinations. Significance: Immunostimulatory chemotherapy combined with pharmacologic inhibition of TAMs results in durable treatment responses elicited by Th cells and B cells in claudin-low TNBC models

Acceptance of Knowledge Management Concepts in Religious Organizations: The Impacts of Information and Willful Disengagement from Productive Inquiry

This study analyzed how churches create cultures in which the recirculating of the same information is encouraged, or cultures in which new information is introduced regularly. It then analyzed how these cultures impact engagement with important knowledge management (KM) principles. Particular attention was paid to the factors that contribute to a church’s decision to engage in a critical questioning of assumed beliefs—productive inquiry (PI)—shown to be an important behavior in successful organizations. In eight, 90- minute focus groups, 28 congregants from Mainline Protestant churches were asked to discuss the information behavior surrounding their religious beliefs. Qualitative coding and analysis revealed that the introduction of shared information produced barriers to PI, and the introduction of unique information encouraged PI. However, congregations were purposive in their decision to either engage or disengage in this inquiry based on organizational goals. Analysis showed that the decision to engage with PI was dependent upon a number of variables. A model is provided that outlines the necessary conditions for a congregation with a goal of either PI, or its conceptual opposite—reaffirmation of existing information and beliefs. This reaffirmation tended to result from a relationship goal, but it is suggested that this relationship goal might be better achieved through PI. This study has important implications for organizations that could benefit from the implementation of KM but are less receptive to its requirements