Cancer research最新文献

The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis and better responses to immune checkpoint blockade in many cancer types. Elucidation of the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to antitumor responses may facilitate the development of improved treatment strategies. Lymphotoxin β receptor (LTβR) signaling is a critical regulator of lymph node organogenesis and can cooperate with antiangiogenic and immune checkpoint blockade treatment to augment tumor-associated HEV formation. In this study, we demonstrated that LTβR signaling modulates the tumor microenvironment via multiple mechanisms to promote antitumor T-cell responses. Systemic activation of the LTβR pathway via agonistic antibody treatment induced tumor-specific HEV formation, upregulated the expression of TLS-related chemokines, and enhanced dendritic cell (DC) and T-cell infiltration and activation in syngeneic tumor models. In vitro studies confirmed direct effects of LTβR agonism on DC activation and maturation and associated DC-mediated T-cell activation. Single-agent LTβR agonist treatment inhibited syngeneic tumor growth in a CD8+ T-cell-dependent and HEV-dependent manner, and the LTβR agonist enhanced antitumor effects of anti-PD-1 and CAR T-cell therapies. An in vivo tumor screen for TLS-inducing cytokines revealed that the combination of LTβR agonism and lymphotoxin ⍺ expression promoted robust intratumoral TLS induction and enhanced tumor responses to anti-CTLA4 treatment. Collectively, this study highlights crucial functions of LTβR signaling in modulating the tumor microenvironment and could inform future HEV/TLS-based strategies for cancer treatments. Significance: LTβR mediates tumor-specific  high endothelial venule formation and immunomodulation of the tumor microenvironment that promotes antitumor immune responses, supporting LTβR agonism as an approach to enhance the antitumor efficacy of immunotherapies.

Osimertinib, a third generation epidermal growth factor receptor tyrosine kinase inhibitor, is approved as a first-line therapy in patients with advanced non-small cell lung carcinoma (NSCLC) with EGFR-activating mutations or the T790M resistance mutation. However, the efficacy of osimertinib is limited due to acquired resistance, highlighting the need to elucidate resistance mechanisms to facilitate the development of improved treatment strategies. Here, we screened for significantly upregulated genes encoding protein kinases in osimertinib-resistant NSCLC cells and identified NUAK1 as a pivotal regulator of osimertinib resistance. NUAK1 was highly expressed in osimertinib-resistant NSCLC and promoted the emergence of osimertinib resistance. Genetic or pharmacological blockade of NUAK1 restored the sensitivity of resistant NSCLC cells to osimertinib in vitro and in vivo. Mechanistically, NUAK1 directly interacted with and phosphorylated nicotinamide adenine dinucleotide kinase (NADK) at serine 64 (S64), which mitigated osimertinib-induced accumulation of reactive oxygen species (ROS) and contributed to the acquisition of osimertinib resistance in NSCLC. Furthermore, virtual drug screening identified T21195 as an inhibitor of NADK-S64 phosphorylation, and T21195 synergized with osimertinib to reverse acquired resistance by inducing ROS accumulation. Collectively, these findings highlight the role of the NUAK1-NADK axis in governing osimertinib resistance in NSCLC and indicate the potential of targeting this axis as a strategy for circumventing resistance. Significance: Phosphorylation of NADK by NUAK1 diminishes ROS accumulation and confers resistance to osimertinib, identifying NUAK1-NADK signaling as a potential therapeutic target for improving the response to EGFR inhibition in lung cancer.

Vδ1T cells, a rare subset of γδT cells, hold promise for treating solid tumors. Unlike conventional T cells, they recognize tumor antigens independently of the MHC antigen presentation pathway, making them a potential "off-the-shelf" cell therapy product. However, isolation and activation of Vδ1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale clinical-grade manufacturing process for Vδ1T cells and validated the therapeutic potential of B7-H3 chimeric antigen receptor (CAR)-modified Vδ1T cells in treating solid tumors. Coexpression of IL2 with the B7-H3-CAR led to durable antitumor activity of Vδ1T cells in vitro and in vivo. In multiple subcutaneous and orthotopic mouse xenograft tumor models, a single intravenous administration of the CAR-Vδ1T cells resulted in complete tumor regression. These modified cells demonstrated significant in vivo expansion and robust homing ability to tumors, akin to natural tissue-resident immune cells. Additionally, the B7-H3-CAR-Vδ1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR-modified Vδ1T cells represent a promising strategy for treating solid tumors. Significance: A clinical-grade expansion protocol enabled generation of B7-H3-targeted CAR-Vδ1T cells with robust anticancer activity and a favorable safety profile, supporting the potential of CAR-Vδ1T cells as an "off-the-shelf" therapy for solid tumors.

The striking ethnic and racial disparities in breast cancer mortality are not explained fully by pathologic or clinical features. Structural racism contributes to adverse conditions that promote cancer inequities, but the pathways by which this occurs are not fully understood. Social determinants of health, such as economic status and access to care, account for a portion of this variability, yet interventions designed to mitigate these barriers have not consistently led to improved outcomes. Based on the current evidence from multiple disciplines, we describe a conceptual model in which structural racism and racial discrimination contribute to increased mortality risk in diverse groups of patients by promoting adverse social determinants of health that elevate exposure to environmental hazards and stress; these exposures in turn contribute to epigenetic and immune dysregulation, thereby altering breast cancer outcomes. Based on this model, opportunities and challenges arise for interventions to reduce racial and ethnic disparities in breast cancer mortality.

Pseudouridylation is a common RNA modification that is catalyzed by the family of pseudouridine synthases (PUS). Pseudouridylation can increase RNA stability and rigidity, thereby impacting RNA splicing, processing, and translation. Given that RNA metabolism is frequently altered in cancer, pseudouridylation may be a functionally important process in tumor biology. Here, we show that the MYC family of oncoproteins transcriptionally upregulates PUS7 expression during cancer development. PUS7 is essential for the growth and survival of MYC-driven cancer cells and xenografts by promoting adaptive stress responses and amino acid biosynthesis and import. ATF4, a master regulator of stress responses and cellular metabolism, was identified as a key downstream mediator of PUS7 functional activity. Induction of ATF4 by MYC oncoproteins and cellular stress required PUS7, and ATF4 overexpression overcame the growth inhibition caused by PUS7 deficiency. Mechanistically, PUS7 induced pseudouridylation of MCTS1 mRNA, which enhanced its translation. MCTS1, a noncanonical translation initiation factor, drove stress-induced ATF4 protein expression. A PUS7 consensus pseudouridylation site in the 3' untranslated region of ATF4 mRNA was crucial for the induction of ATF4 by cellular stress. These findings unveil an MYC-activated mRNA pseudouridylation program that mitigates cellular stress induced by MYC stimulation of proliferation and biomass production, suggesting that targeting PUS7 could be a therapeutic strategy selectively against MYC-driven cancers. Significance: Oncogene activation of mRNA pseudouridylation is a mechanism that facilitates metabolic reprogramming and adaptive responses to overcome cellular stress during cancer development.

Extracellular vesicles (EV) derived from cancer cells are crucial mediators of intercellular communication during tumor progression. The cargo in tumor-derived EVs that facilitates the establishment of a tumor-supportive microenvironment could serve as a therapeutic target to improve cancer treatment. Here, we demonstrated that hepatocellular carcinoma (HCC) cells secreted the acyl-CoA synthetase long-chain family member 4 (ACSL4) in large EVs (lEV) to modulate tumor-microenvironment interactions that promote HCC progression. HCC-derived lEV ACSL4 increased the intracellular abundance of polyunsaturated fatty acid-containing lipids and remodeled the lipid profile to potentiate lipid peroxidation in peritumoral hepatocytes, resulting in hepatocyte senescence accompanied by the senescence-associated secretory phenotype. Depletion of senescent hepatocytes by senolytic treatment suppressed tumor progression. In HCC cells, SREBP2-mediated transcriptional activation upregulated ACSL4 expression, and Akt-mediated phosphorylation of ACSL4 induced its packaging into lEVs by augmenting its interaction with Annexin A2. This study identified the critical regulatory function of ACSL4 secreted from HCC cells in inducing lipid remodeling and senescence in hepatocytes to support HCC progression, suggesting that targeting lEV ACSL4 is a potential therapeutic strategy for HCC. Significance: Peritumoral hepatocyte senescence mediated by ACSL4 secreted from hepatocellular carcinoma cells in extracellular vesicles promotes tumor progression through a senescence secretome and represents a therapeutic target in liver cancer.