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Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC).sup.1. The extracellular matrix (ECM) contributes to immune exclusion.sup.2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes.sup.3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity.sup.5, 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., Author(s): Xiujie Sun [sup.1] , Bogang Wu [sup.1] , Huai-Chin Chiang [sup.1] , Hui Deng [sup.2] , Xiaowen Zhang [sup.1] , Wei Xiong [sup.2] , Junquan Liu [sup.2] , Aaron [...]

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]

A recent Nature study delineates a stepwise genomic evolution during pancreatic cancer development, employing an engineered mutant Kras and heterozygous Trp53 mouse model that identifies cells undergoing Trp53 loss of heterozygosity (LOH). Genetic progression post- Trp53 LOH involves clonal deletions, then genome doubling and subsequent accumulation of subclonal gains and amplifications. [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]

More attention has recently been focused on the treatment of various kinds of hepatic diseases based on cell-based therapies. In this study, mesenchymal stem cells were isolated from umbilical cord (UC-MSCs). Results confirmed that UC-MSCs could differentiate into adipocytes, osteoblasts and hepatocytes. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) (PHBVHHx), a new member of polyhydroxyalkanoate (PHA) family, was produced by bacteria. Liver-injured mouse model was established by CCl4 injection. PHBVHHx scaffolds were transplanted into the liver-injured mice. Liver morphology on day 28 post-transplantation of scaffolds loaded with UC-MSCs or hepatocyte-like cells differentiated from UC-MSCs significantly improved and looked similar to the normal liver. Concentrations of albumin (ALB) significantly increased, and total bilirubin (TB) and alanine axminotransferase (ALT) significantly decreased on days 14 and 28 post-transplantation of scaffolds loaded with UC-MSCs or differentiated UC-MSCs. HE staining showed that on day 28 post-transplantation of scaffolds loaded with UC-MSCs or differentiated UC-MSCs, livers had similar tissue structure of normal livers. Masson staining showed that on day 28 post-transplantation of scaffolds loaded with UC-MSCs or differentiated UC-MSCs, livers had less blue staining for collagen deposition compared with the others. These results demonstrated that PHBVHHx scaffolds loaded with UC-MSCs or differentiated UC-MSCs had the similar effect on injured livers and significantly promoted the recovery of injured livers. [ABSTRACT FROM AUTHOR]

Purpose: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) comprises the topoisomerase 1 (TOP1) inhibitor (TOP1i) SN-38, coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2). Poly(ADP-ribose) polymerase (PARP) inhibition may synergize with TOP1i and SG, but previous studies combining systemic PARP and TOP1 inhibitors failed due to dose-limiting myelosuppression. Here, we assess the proof-of-mechanism and clinical feasibility for SG and talazoparib (TZP) employing an innovative sequential dosing schedule., Patients and Methods: In vitro models tested pharmacodynamic endpoints, and in a phase 1b clinical trial (NCT04039230), 30 patients with metastatic triple-negative breast cancer (mTNBC) received SG and TZP in a concurrent (N = 7) or sequential (N = 23) schedule. Outcome measures included safety, tolerability, preliminary efficacy, and establishment of a recommended phase 2 dose., Results: We hypothesized that tumor-selective delivery of TOP1i via SG would reduce nontumor toxicity and create a temporal window, enabling sequential dosing of SG and PARP inhibition. In vitro, sequential SG followed by TZP delayed TOP1 cleavage complex clearance, increased DNA damage, and promoted apoptosis. In the clinical trial, sequential SG/TZP successfully met primary objectives and demonstrated median progression-free survival (PFS) of 7.6 months without dose-limiting toxicities (DLT), while concurrent dosing yielded 2.3 months PFS and multiple DLTs including severe myelosuppression., Conclusions: While SG dosed concurrently with TZP is not tolerated clinically due to an insufficient therapeutic window, sequential dosing of SG followed by TZP proved a viable strategy. These findings support further clinical development of the combination and suggest that ADC-based therapy may facilitate novel, mechanism-based dosing strategies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Women with BRCA1 germline mutations have approximately an 80% lifetime chance of developing breast cancer. While the tumor suppressor function of BRCA1 in breast epithelium has been studied extensively, it is not clear whether BRCA1 deficiency in non-breast somatic cells also contribute to tumorigenesis. Here, we report that mouse Brca1 knockout (KO) in mature T lymphocytes compromises host antitumor immune response to transplanted syngeneic mouse mammary tumors. T cell adoptive transfer further corroborates CD8 + T cell-intrinsic impact of Brca1 KO on antitumor adaptive immunity. T cell-specific Brca1 KO mice exhibit fewer total CD8 + , more exhausted, reduced cytotoxic, and reduced memory tumor-infiltrating T cell populations. Consistent with the preclinical data, cancer-free BRCA1 mutation-carrying women display lower abundance of circulating CD8 + lymphocytes than the age-matched control group. Thus, our findings support the notion that BRCA1 deficiency in adaptive immunity could contribute to BRCA1 -related tumorigenesis. We also suggest that prophylactic boosting of adaptive immunity may reduce cancer incidence among at-risk women., Competing Interests: Competing interests: Claudine Isaacs: Consultancies: Genentech, PUMA, Seagen, AstraZeneca, Novartis, Pfizer, ION; Gilead; Royalties: Wolters Kluwer (UptoDate); McGraw Hill (Goodman and Gillman); Research support (to institution): Tesaro/GSK; Seattle Genetics; Pfizer; AZ; BMS; Genentech; Novartis.Rong Li: Scientific advisory board of Parthenon Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

BackgroundThe non-overlapping functions of the two estrogen receptor subtypes, ERα (Estrogen Receptor α)and ERβ (Estrogen Receptor β), in tumor cells have been studied extensively. However, their counterparts in host cells is vastly underinterrogated. Even less is known about how ERα and ERβ activities are regulated in a subtype-specific manner. We previously identified a phosphotyrosine residue (pY36) of human ERβ that is important for tumor ERβ to inhibit growth of breast cancer cells in vitro and in vivo. A role of this ERβ phosphotyrosine switch in regulating host ERβ remains unclear.Conventional gene editing was used to mutate the corresponding tyrosine residue of endogenous mouse ERβ (Y55F) in mouse embryonic stem cells. The derived homozygous mutant Esr2 Y55F/Y55F mouse strain and its wild-type (WT) counterpart were compared in various transplant tumor models for their ability to support tumor growth. In addition, flow cytometry-based immunophenotyping was carried out to assess antitumor immunity of WT and mutant hosts. Adoptive transfer of bone marrow and purified CD8 + T cells were performed to identify the host cell type that harbors ERβ-dependent antitumor function. Furthermore, cell signaling assays were conducted to compare T cell receptor (TCR)-initiated signaling cascade in CD8 + T cells of WT and mutant mice. Lastly, the ERβ-selective agonist S-equol was evaluated for its efficacy to boost immune checkpoint blockade (ICB)-based anticancer immunotherapy.Disabling the ERβ-specific phosphotyrosine switch in tumor-bearing hosts exacerbates tumor growth. Further, a cell-autonomous ERβ function was defined in CD8 + effector T cells. Mechanistically, TCR activation triggers ERβ phosphorylation, which in turn augments the downstream TCR signaling cascade via a non-genomic action of ERβ. S-equol facilitates TCR activation that stimulates the ERβ phosphotyrosine switch and boosts anti-PD-1 (Programmed cell death protein 1) ICB immunotherapy.Our mouse genetic study clearly demonstrates a role of the ERβ phosphotyrosine switch in regulating ERβ-dependent antitumor immunity in CD8 + T cells. Our findings support the development of ERβ agonists including S-equol in combination with ICB immunotherapy for cancer treatment., Competing Interests: Competing interests: TC, BY and RL are inventors on a patent for S-equol., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

The programmed death-ligand 1 (PD-L1)-dependent immune checkpoint attenuates host immunity and maintains self-tolerance. Imbalance between protective immunity and immunopathology due to altered PD-L1 signaling can lead to autoimmunity or tumor immunosuppression. The role of the PD-L1-dependent checkpoint in non-immune system is less reported. We previously found that white adipocytes highly express PD-L1. Here we show that adipocyte-specific PD-L1 knockout mice exhibit enhanced host anti-tumor immunity against mammary tumors and melanoma with low or no tumor PD-L1. However, adipocyte PD-L1 ablation in tumor-free mice also exacerbates diet-induced body weight gain, pro-inflammatory macrophage infiltration into adipose tissue, and insulin resistance. Low PD-L1 mRNA levels in human adipose tissue correlate with high body mass index and presence of type 2 diabetes. Therefore, our mouse genetic approach unequivocally demonstrates a cell-autonomous function of adipocyte PD-L1 in promoting tumor growth and inhibiting antitumor immunity. In addition, our work uncovers a previously unrecognized role of adipocyte PD-L1 in mitigating obesity-related inflammation and metabolic dysfunction., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint blockade-based immunotherapy has become standard of care for multiple cancer types. However, the overall response rates among various cancer types still remain unsatisfactory. There is a pressing clinical need to identify combination therapies to improve efficacy of anticancer immunotherapy. We previously showed that pharmacologic inhibition of PPARγ by GW9662 boosts αPD-L1 and αPD-1 antibody efficacy in treating murine mammary tumors. In addition, we defined sexually dimorphic αPD-L1 efficacy in B16 melanoma. Here, we show a sexually dimorphic response to the combination of GW9662 and αPD-L1 immunotherapy in B16 melanoma. Combination effects were observed in female, but not male hosts. Neither female oöphorectomy impairs, nor does male castration rescue the combination effects, suggesting a sex hormone-independent response to this combination therapy. In diet-induced obese females, melanoma growth remained responsive to the combination treatment, albeit less robustly than lean females. These findings are informative for future design and application of immunotherapy-related combination therapy for treating human melanoma patients by taking gender and obesity status into consideration., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communication with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in the stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear. Here we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice. We also found that the tumor-associated stroma in Ddr1- KO mice exhibits reduced collagen deposition compared with the WT controls, supporting a role for stromal DDR1 in ECM remodeling of the tumor microenvironment. Furthermore, the stromal-vascular fraction (SVF) of Ddr1 knockout adipose tissue, which contains committed adipose stem/progenitor cells and preadipocytes, was impaired in its ability to stimulate tumor cell migration and invasion. Cytokine array-based screening identified interleukin 6 (IL-6) as a cytokine secreted by the SVF in a DDR1-dependent manner. SVF-produced IL-6 is important for SVF-stimulated tumor cell invasion in vitro , and, using antibody-based neutralization, we show that tumor promotion by IL-6 in vivo requires DDR1. In conclusion, our work demonstrates a previously unrecognized function of DDR1 in promoting tumor growth., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)