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Background. Cytokinesthat promote wound healing and immune tolerance are profoundly upregulated during post-lactational involution of the breast and promote tumor growth and malignancy. This observation is supported by increasing evidence that post-lactational involution produces a highly malignant microenvironment contributing to poor outcome of pregnancy associated breast cancers (PABCs) which arise within 5 years of a full-term pregnancy. We have discovered that one mechanism driving cytokine modulation during post-lactational involution is efferocytosis, or the phagocytic clearance of apoptotic cells (ACs). Cell death is a prominent feature of the post-lactational breast, when up to 90% of the entire epithelial content dies and must be removed, making this an ideal model to study both apoptosis and AC clearance. Without efferocytosis, residual ACs undergo secondary necrosis, which stimulates acute inflammation and expression of Th1 cytokines. Thus, efferocytosis prevents secondary necrosis of dying cells, enhances immune tolerance and wound healing through production of Th2 cytokines. In healthy post-lactational breast tissue this is an optimal physiological response that promotes breast remodeling. However, in the context of breast cancer, efferocytosis may be pro-tumorigenic. Results. We have shown that post-lactational efferocytosis is necessary to re-establish breast tissue homeostasis after lactation, and for re-initiating successful lactation after future pregnancies. We have also demonstrated that during the earliest phases of post-lactational involution, the breast epithelium is the primary phagocytic resource in the breast, although it is clear that macrophages engulf dying cells during later stages of involution. We have identified the receptor tyrosine kinase MerTK as a necessary mediator of efferocytosis and subsequent cytokine modulation during post-lactational involution. Further, MerTK-mediated cytokine changes in the post-lactational mammary microenvironment promotes malignant progression of spontaneously forming PABC in a transgenic mouse model, as genetic targeting of MerTK decreased tumor growth and metastasis without altering tumor latency. Post-lactational tumors expressed abundant Th2 and wound healing cytokines as compared to tumors in nulliparous mice. However, loss of MerTK in post-lactational mammary tumors impaired the expression of Th2 and wound healing cytokines, while inducing the expression of Th1 cytokines. Conclusion. These results suggest that efferocytosis-mediated cytokine regulation is a key driver of malignant severity in pregnancy associated mammary tumors. These data are consistent with our previous demonstrations that MerTK in the mammary tumor microenvironment increases tumor malignancy. Targeted inhibition of MerTK may decrease efferocytosis-mediated cytokine modulation in breast tumors to limit pro-tumorigenic cytokine production and stimulate production of cytokines associated with anti-tumor immunity. [ABSTRACT FROM AUTHOR]

The receptor tyrosine kinase MERTK is aberrantly expressed in numerous human malignancies, and is a novel target in cancer therapeutics. Physiologic roles of MERTK include regulation of tissue homeostasis and repair, innate immune control, and platelet aggregation. However, aberrant expression in a wide range of liquid and solid malignancies promotes neoplasia via growth factor independence, cell cycle progression, proliferation and tumor growth, resistance to apoptosis, and promotion of tumor metastases. Additionally, MERTK signaling contributes to an immunosuppressive tumor microenvironment via induction of an anti-inflammatory cytokine profile and regulation of the PD-1 axis, as well as regulation of macrophage, myeloid-derived suppressor cell, natural killer cell and T cell functions. Various MERTK-directed therapies are in preclinical development, and clinical trials are underway. In this review we discuss MERTK inhibition as an emerging strategy for cancer therapy, focusing on MERTK expression and function in neoplasia and its role in mediating resistance to cytotoxic and targeted therapies as well as in suppressing anti-tumor immunity. Additionally, we review preclinical and clinical pharmacological strategies to target MERTK., Competing Interests: Declaration of Competing Interest Diana Fridlyand – The author declares that there are no conflicts of interest Justus Huelse – The author declares that there are no conflicts of interest Shelton Earp – The author holds equity in Meryx incorporated and is on the Meryx board of directors Deborah DeRyckere – The author holds equity in Meryx incorporated Douglas K. Graham – The author holds equity in Meryx incorporated and is on the Meryx board of directors, (Copyright © 2020 Elsevier Inc. All rights reserved.)

Tumor-derived paracrine signaling is an overlooked component of local immunosuppression and can lead to a permissive environment for continued cancer growth and metastasis. Paracrine signals can involve cell-cell contact between different cell types, such as PD-L1 expressed on the surface of tumors interacting directly with PD-1 on the surface of T cells, or the secretion of ligands by a tumor cell to affect an immune cell. Here we describe a co-culture method to interrogate the effects of tumor-secreted ligands on immune cell (macrophage) activation. This straightforward procedure utilizes commercially available 0.4 µm polycarbonate membrane permeable supports and standard tissue culture plates. In the process described, macrophages are cultured in the upper chamber and tumor cells in the lower chamber. The presence of the 0.4 µm barrier allows for the study of intercellular signaling without the confounding variable of physical contact, because the two cell types share the same medium and exposure to paracrine ligands. This approach can be combined with others, such as genetic alterations of the macrophage (e.g., isolation from genetic knock-out mice) or tumor (e.g., CRISPR-mediated alterations) to study the role of specific secreted factors and receptors. The approach also lends itself to standard molecular biological analyses such as quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blot analysis, without the need for flow sorting to separate the two cell populations. Enzyme-linked immunosorbent assays (ELISAs) can similarly be utilized to measure secreted ligands to better understand the dynamic interaction of cell signaling in the multiple cell type context. Duration of co-culture can also be varied for the study of temporally regulated events. This co-culture method is a robust tool that facilitates the study of tumor-secreted signals in the immune context.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race. This study examined the relationship between race and admission service, and its effect on 30-day readmission and mortality Methods: We performed a retrospective cohort study from September 2008 to November 2017 at a single large urban academic referral center of all patients self-referred to the emergency department and admitted to either the cardiology or general medicine service with a principal diagnosis of HF, who self-identified as white, black, or Latinx. We used multivariable generalized estimating equation models to assess the relationship between race and admission to the cardiology service. We used Cox regression to assess the association between race, admission service, and 30-day readmission and mortality., Results: Among 1967 unique patients (66.7% white, 23.6% black, and 9.7% Latinx), black and Latinx patients had lower rates of admission to the cardiology service than white patients (adjusted rate ratio, 0.91; 95% CI, 0.84-0.98, for black; adjusted rate ratio, 0.83; 95% CI, 0.72-0.97 for Latinx). Female sex and age >75 years were also independently associated with lower rates of admission to the cardiology service. Admission to the cardiology service was independently associated with decreased readmission within 30 days, independent of race., Conclusions: Black and Latinx patients were less likely to be admitted to cardiology for HF care. This inequity may, in part, drive racial inequities in HF outcomes.