Staphylococcus aureus can induce trained immunity in murine macrophages offering protection against repeat exposure during S. aureus skin infection. Here we demonstrate that S. aureus exposure can result in non-specific trained immunity in humans and mice, enhancing macrophage responsiveness and bacterial clearance in a heterologous challenge. In humans, the enhanced macrophage responsiveness was accompanied by metabolic changes and histone modification. In mice, the enhanced responsiveness of macrophages occurred in conjunction with enhanced myelopoiesis. This report provides further insights on the host's response to the bacterium S. aureus, indicating that exposure to this organism induces heterologous protection against subsequent gram-negative infection that is provided by macrophages. These findings support the hypothesis that S. aureus has evolved to develop a mutualistic relationship with the host, imbuing the host with enhanced capacity to protect itself from attack by alternative pathogens, while potentially allowing S. aureus to exert its dominance within its niche.
© 2024 The Authors.

Abstract Bladder cancer is recognized as one of the most prevalent malignant tumors within the urinary system. The conventional treatment approach for bladder cancer typically involves a combination of surgery, radiotherapy, and chemotherapy. However, the efficacy of current treatment modalities remains suboptimal, prompting ongoing efforts to develop novel and more effective therapeutic strategies to better address the clinical demands of bladder cancer management. In this study, we utilized the orthotopic mouse model to assess the effectiveness of intravesical conventional chemotherapy alone and in combination with immunotherapy for treating bladder cancer. The anti-tumor effect was analyzed by determining bioluminescence imaging (BLI), while histopathological analysis was conducted to evaluate the tumor proliferation and invasion capabilities upon treatment. Additionally, alterations in the immune microenvironment within different treatment methods were studied through flow cytometry for various T-cell markers. BLI and tumor weights analysis revealed that the intravesical route of doxorubicin administration produced better treatment efficacy than the conventional chemotherapy through the intraperitoneal route and combination of doxorubicin and anti-PD-L1 i.p administration. Histopathological analysis and proliferation markers (Ki-67 staining) revealed significant differences across the intravesical, conventional chemotherapy, and immune combination therapy groups. Importantly, intravesical treatment was more effective in reducing tumor cell proliferation compared to the other groups. FACS analysis revealed the route of administration significantly impacted the immune response in the tumor microenvironment. Our results demonstrate that both intravesical and conventional doxorubicin chemotherapy led to a significant decrease in CD8+ T cell expression (p < 0.01), while intravesical treatment exhibited a more pronounced activation of CD8+ T cells, as evidenced by increased CD69 expression. Treg cells also showed moderate reductions in the conventional chemotherapy and immune combination therapy groups. Notably, the intravesical approach activated CD8+ T cells more effectively and reduced the expression of the exhaustion marker PD-1 compared to immune combination therapy. Overall, these findings highlight the potential of intravesical doxorubicin delivery to activate CD8+ T cells and reduce immune exhaustion, enhancing its anti-tumor efficacy. These results suggest that intravesical administration may be a viable treatment option for bladder cancer in clinical settings.

Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIF). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell lines and common breast cancer cell lines, hypoxia downregulated tumor-intrinsic type I IFN signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a "hypoxic memory" phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for circulating tumor cells during the metastatic cascade. Significance: Long-term cellular memory of hypoxia leads to sustained suppression of tumor-intrinsic type I IFN signaling and the antigen presentation pathway that facilitates tumorigenesis and metastasis. See related commentary by Purdy and Ford, p. 3125.
©2024 American Association for Cancer Research.

Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear.
The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells.
APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1.
APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma.
© 2024. The Author(s).

Abstract Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutical opportunities. Here, we identified a novel subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity.  Mechanistically, succinate secreted by tumor-associated PreNeu inhibits homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability, promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro and in vivo. Tumor-associated PreNeu score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumorigenic effect of these neutrophils and synergize with combined immunotherapeutic approaches.