Search

Simple Summary: In cancer, CD8+ T cells enter a state of dysfunction within the tumor that prevents them from targeting and killing tumor cells. Our study aims to uncover how CD8+ T cells can be helped by CD4+ T cells or modified in order to improve their effector function against cancer. Thus, allowing them to better fight and control tumors. Our work shows that the protein Basic Leucine Zipper ATF-Like Transcription Factor (BATF) may be a key regulator of CD8+ T cells and their anti-tumor function. These findings can provide further insight for the development of novel therapeutic treatments for cancer patients. In cancer, CD8+ T cells enter a dysfunctional state which prevents them from effectively targeting and killing tumor cells. Tumor-infiltrating CD8+ T cells consist of a heterogeneous population of memory-like progenitor, effector, and terminally exhausted cells that exhibit differing functional and self-renewal capacities. Our recently published work has shown that interleukin (IL)-21-producing CD4+ T cells help to generate effector CD8+ T cells within the tumor, which results in enhanced tumor control. However, the molecular mechanisms by which CD4+ helper T cells regulate the differentiation of effector CD8+ T cells are not well understood. In this study, we found that Basic Leucine Zipper ATF-Like Transcription Factor (BATF), a transcription factor downstream of IL-21 signaling, is critical to maintain CD8+ T cell effector function within the tumor. Using mixed bone marrow chimeras, we demonstrated that CD8+ T cell-specific deletion of BATF resulted in impaired tumor control. In contrast, overexpressing BATF in CD8+ T cells enhanced effector function and resulted in improved tumor control, bypassing the need for CD4+ helper T cells. Transcriptomic analyses revealed that BATF-overexpressing CD8+ T cells had increased expression of costimulatory receptors, effector molecules, and transcriptional regulators, which may contribute to their enhanced activation and effector function. Taken together, our study unravels a previously unappreciated CD4+ T cell-derived IL-21–BATF axis that could provide therapeutic insights to enhance effector CD8+ T cell function to fight cancer. [ABSTRACT FROM AUTHOR]

Constitutively active mutations of KRAS are prevalent in non-small cell lung cancer (NSCLC). However, the relationship between these mutations and resistance to platinum-based chemotherapy and the underlying mechanisms remain elusive. In this study, we demonstrated that KRAS mutants confer resistance to platinum in NSCLC. Mechanistically, KRAS mutants mediate platinum resistance in NSCLC cells by activating ERK/JNK signaling, which inhibits ALKBH5 m6A demethylase activity by regulating post-translational modifications (PTMs) of ALKBH5. Consequently, the KRAS mutant leads to a global increase in m6A methylation of mRNAs, particularly DDB2 and XPC, which are essential for nucleotide excision repair. This methylation stabilized the mRNA of these two genes, thus enhancing NSCLC cells' ability to repair platinum-induced DNA damage and avoid apoptosis, thereby contributing to drug resistance. Furthermore, blocking KRAS-mutant-induced m6A methylation, either by overexpressing a SUMOylation-deficient mutant of ALKBH5, or by inhibiting METTL3 pharmacologically, significantly sensitizes KRAS-mutant NSCLC cells to platinum drugs in vitro and in vivo. Collectively, our study uncovers a previously unrecognized mechanism that mediates KRAS mutant-induced chemoresistance in NSCLC cells by activating DNA repair through the modulation of the ERK/JNK/ALKBH5 PTMs-induced m6A modification in DNA damage repair-related genes.

The increase in bacterial antibiotic resistance poses a significant threat to the effectiveness of antibiotics, and there is growing evidence suggesting that global warming may speed up this process. However, the direct influence of temperature on the development of antibiotic resistance and the underlying mechanisms is not yet fully understood. Here we show that antibiotic resistance exhibits a nonlinear response to elevated temperatures under the combined stress of temperatures and antibiotics. We find that the effectiveness of gatifloxacin against Escherichia coli significantly diminishes at 42 °C, while resistance increases 256-fold at 27 °C. Additionally, the increased transcription levels of genes such as marA , ygfA , and ibpB with rising temperatures, along with gene mutations at different sites, explain the observed variability in resistance patterns. These findings highlight the complexity of antibiotic resistance evolution and the urgent need for comprehensive studies to understand and mitigate the effects of global warming on antibiotic resistance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V. on behalf of Chinese Society for Environmental Sciences, Harbin Institute of Technology, Chinese Research Academy of Environmental Sciences.)