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Simple Summary: Antibody–drug conjugates (ADCs) are a growing class of therapies that aim to delivery therapy more efficiently, with fewer side effects, than conventional chemotherapy. ADCs are composed of an antibody linked to a chemotherapy payload, allowing targeted delivery of the chemotherapy. In the last decade, several antibody–drug conjugates have improved treatment options in breast cancer. However, patients usually progress on these agents, and more research is needed into why this resistance occurs. Given the complex structure of antibody-drug conjugates, resistance may be related to changes in antigen expression, ADC processing, and the chemotherapy payload. This paper reviews the literature on the mechanisms of resistance to antibody–drug conjugates including pre-clinical and clinical studies in breast cancer and other malignancies. This review includes information on ADCs that have been approved for use in breast cancer and ADCs in development that seek to overcome the proposed mechanisms of resistance to improve treatment options for patients. Antibody–drug conjugates (ADCs), with antibodies targeted against specific antigens linked to cytotoxic payloads, offer the opportunity for a more specific delivery of chemotherapy and other bioactive payloads to minimize side effects. First approved in the setting of HER2+ breast cancer, more recent ADCs have been developed for triple-negative breast cancer (TNBC) and, most recently, hormone receptor-positive (HR+) breast cancer. While antibody–drug conjugates have compared favorably against traditional chemotherapy in some settings, patients eventually progress on these therapies and require a change in treatment. Mechanisms to explain the resistance to ADCs are highly sought after, in hopes of developing next-line treatment options and expanding the therapeutic windows of existing therapies. These resistance mechanisms are categorized as follows: change in antigen expression, change in ADC processing and resistance, and efflux of the ADC payload. This paper reviews the recently published literature on these mechanisms as well as potential options to overcome these barriers. [ABSTRACT FROM AUTHOR]

T cell factor 1 (TCF1) is required for memory and stem-like CD8+ T cell functions. How TCF1 partners with other transcription factors to regulate transcription remains unclear. Here we show that negative elongation factor (NELF), an RNA polymerase II (Pol II) pausing factor, cooperates with TCF1 in T cell responses to cancer. Deletion of mouse Nelfb, which encodes the NELFB subunit, in mature T lymphocytes impairs immune responses to both primary tumor challenge and tumor antigen-mediated vaccination. Nelfb deletion causes more exhausted and reduced memory T cell populations, whereas its ectopic expression boosts antitumor immunity and efficacy of chimeric antigen receptor T-cell immunotherapy. Mechanistically, NELF is associated with TCF1 and recruited preferentially to the enhancers and promoters of TCF1 target genes. Nelfb ablation reduces Pol II pausing and chromatin accessibility at these TCF1-associated loci. Our findings thus suggest an important and rate-limiting function of NELF in anti-tumor immunity. Negative elongation factor B (NELFB) is one of the four subunits of the NELF complex that controls RNA polymerase II pausing. Here the authors show that, by associating with the key T cell transcription factor TCF1, NELFB is required for eliciting CD8 + T cell memory and anti-tumor immune responses. [ABSTRACT FROM AUTHOR]

Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)1. The extracellular matrix (ECM) contributes to immune exclusion2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity5, instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.In mouse models of triple-negative breast cancer, the extracellular domain of the collagen receptor DDR1 has a role in tumour defence against the immune system, by aligning collagen fibres to obstruct immune infiltration. [ABSTRACT FROM AUTHOR]

Tumor cell‐intrinsic programmed death‐ligand 1 (PD‐L1) signals mediate immunopathologic effects in breast, colon, and ovarian cancers and in melanomas, but bladder cancer (BC) effects are unreported. We show here that BC cell‐intrinsic PD‐L1 signals in mouse MB49 and human RT4, UM‐UC3, and UM‐UC‐14 BC cells regulate important pathologic pathways and processes, including effects not reported in other cancers. α‐PD‐L1 antibodies reduced BC cell proliferation in vitro, demonstrating direct signaling effects. BC cell‐intrinsic PD‐L1 promoted mammalian target of rapamycin complex 1 (mTORC1) signals in vitro and augmented in vivo immune‐independent cell growth and metastatic cancer spread, similar to effects we reported in melanoma and ovarian cancer. BC cell‐intrinsic PD‐L1 signals also promoted basal and stress‐induced autophagy, whereas these signals inhibited autophagy in melanoma and ovarian cancer cells. BC cell‐intrinsic PD‐L1 also mediated chemotherapy resistance to the commonly used BC chemotherapy agents cis‐platinum and gemcitabine and to the mTORC1 inhibitor, rapamycin. Thus, BC cell‐intrinsic PD‐L1 signals regulate important virulence and treatment resistance pathways that suggest novel, actionable treatment targets meriting additional studies. As a proof‐of‐concept, we showed that the autophagy inhibitor chloroquine improved cis‐platinum treatment efficacy in vivo, with greater efficacy in PD‐L1 null versus PD‐L1‐replete BC. [ABSTRACT FROM AUTHOR]

Phase change materials (PCMs) require an excellent matrix support material such as porous carbon materials. Orange peel, a discarded, readily available raw material, could potentially be used to prepare biological porous carbon material (BPCM) with abundant pores of uniform size and strong loading capacity through a vacuum freeing method and a carbonization process under nitrogen atmosphere. Herein, paraffin (PA) was encapsulated into BPCM by vacuum impregnation method to obtain environmentally friendly; recyclable PA/carbonized-abandoned orange peel (CAOP) shape-stable PCMs (PA/CAOP SS-PCMs). CAOP was composed of amorphous carbon and a certain degree of graphitization occurred, the best of which was observed following carbonization at 1000 °C. Further, at this temperature, the pores were abundant and PA loading was sufficient. PA/CAOP SS-PCMs were shown to undergo simple physical loading with no chemical interactions and to have good thermal stability and a maximum loading percentage of 88.46%; the calculated maximum loading percentage was of 88.07%. The temperature and latent heat during the melting of PA/CAOP SS-PCMs were 47.68 °C and 180.25 J/g, respectively, and the solidification process occurred 34.47 °C and 177.55 J/g, respectively. The composite exhibited excellent thermal stability and reliability after 200 thermal cycles. Therefore, it has very broad application prospects and value in the fields of energy saving and emission reduction, including solar energy, air conditioning storage cooling systems, and building cladding. [ABSTRACT FROM AUTHOR]

Innovative syntheses of uniform and size-controlled chlorapatite crystals need to be developed. Molten salt synthesis is a simple process, which uses low temperatures and short reaction times to obtain synthesized powders with uniform chemical composition as well as good crystal morphology and high-phase purity. In this study, a molten salt synthesis was used to prepare ClAP microcrystallites at different temperatures, reaction times, and quantities of molten salt. ClAP microcrystallites with different sizes and morphologies were obtained, and the process parameters were optimized. The phase formation and morphologies of the ClAP microcrystallites were examined by X-ray powder diffraction and scanning electron microscopy. The results determined the optimal parameters, as follows: synthesis temperature, 600 °C; reaction time, 4 h; and ClAP/molten salt ratio, 1 : 3. The reaction time and the quantity of the molten salt, as well as the growth mechanism of the ClAP microcrystallites, were proposed based on the phase formation and morphologies of ClAP synthesized at various temperatures. ClAP phosphors activated using different ions (Sb3+, Eu2+, and Tb3+) were prepared by the molten salt method at 600 °C for 4 h with a ClAP/salt ratio of 1 : 3. The as-prepared ClAP:Sb3+/Eu2+/Tb3+ phosphors exhibited a blue-green emission (470 nm), a blue emission (460 nm), and a green emission (547 nm). Their excellent photoluminescence properties indicated their potential for application in white light emitting diodes. [ABSTRACT FROM AUTHOR]

Balance between the hematopoietic stem cell (HSC) duality to either possess self-renewal capacity or differentiate into multipotency progenitors (MPPs) is crucial for maintaining homeostasis of the hematopoietic stem/progenitor cell (HSPC) compartment. To retain the HSC self-renewal activity, KIT, a receptor tyrosine kinase, in HSCs is activated by its cognate ligand KITLG originating from niche cells. Here, we show that AT-rich interaction domain 4B (ARID4B) interferes with KITLG/KIT signaling, consequently allowing HSC differentiation. Conditional Arid4b knockout in mouse hematopoietic cells blocks fetal HSC differentiation, preventing hematopoiesis. Mechanistically, ARID4B-deficient HSCs self-express KITLG and overexpress KIT. As to downstream pathways of KITLG/KIT signaling, inhibition of Src family kinases rescues the HSC differentiation defect elicited by ARID4B loss. In summary, the intrinsic ARID4B-KITLG/KIT-Src axis is an HSPC regulatory program that enables the differentiation state, while KIT stimulation by KITLG from niche cells preserves the HSPC undifferentiated pool. [Display omitted] • HSCs with ARID4B deficiency self-express KITLG and overexpress KIT • Autocrine KITLG/KIT signaling phosphorylates Src and blocks HSC differentiation • Src inhibition rescues the HSC differentiation defect caused by ARID4B ablation Hematopoietic stem cells (HSCs) at the top of the hematopoietic hierarchy are able to self-renew and differentiate to mature blood cells. Young et al. report that an HSC self-control mechanism established by ARID4B ensures HSC differentiation. ARID4B-deficient HSCs produce KITLG to stimulate KIT, leading to blockage of HSC differentiation and eventual hematopoietic failure. [ABSTRACT FROM AUTHOR]

Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression. [ABSTRACT FROM AUTHOR]