The immune cells play an increasingly vital role in influencing the proliferation, progression, and metastasis of lung adenocarcinoma (LUAD) cells. However, the potential of immune cells' specific genes‐based model remains largely unknown. In the current study, by analysing single‐cell RNA sequencing (scRNA‐seq) data and bulk RNA sequencing data, the tumour‐infiltrating immune cell (TIIC) associated signature was developed based on a total of 26 machine learning (ML) algorithms. As a result, the TIIC signature score could predict survival outcomes of LUAD patients across five independent datasets. The TIIC signature score showed superior performance to 168 previously established signatures in LUAD. Moreover, the TIIC signature score developed by the immunofluorescence staining of the tissue array of LUAD patients showed a prognostic value. Our research revealed a solid connection between TIIC signature score and tumour immunity as well as metabolism. Additionally, it has been discovered that the TIIC signature score can forecast genomic change, chemotherapeutic drug susceptibility, and—most significantly—immunotherapeutic response. As a newly demonstrated biomarker, the TIIC signature score facilitated the selection of the LUAD population who would benefit from future clinical stratification.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/cpr.13409

An artificial intelligence network‐guided signature for predicting outcome and immunotherapy response in lung adenocarcinoma patients based on 26 machine learning algorithms

Acute myeloid leukaemia (AML) carrying nucleophosmin (NPM1) mutations has been defined as a distinct entity of acute leukaemia. Despite remarkable improvements in diagnosis and treatment, the long-term outcomes for this entity remain unsatisfactory. Emerging evidence suggests that leukaemia, similar to other malignant diseases, employs various mechanisms to evade killing by immune cells. However, the mechanism of immune escape in NPM1-mutated AML remains unknown. In this study, both serum and leukemic cells from patients with NPM1-mutated AML impaired the immune function of CD8+ T cells in a co-culture system. Mechanistically, leukemic cells secreted miR-19a-3p into the tumour microenvironment (TME) via small extracellular vesicles (sEVs), which was controlled by the NPM1-mutated protein/CCCTC-binding factor (CTCF)/poly (A)-binding protein cytoplasmic 1 (PABPC1) signalling axis. sEV-related miR-19a-3p was internalized by CD8+ T cells and directly repressed the expression of solute-carrier family 6 member 8 (SLC6A8; a creatine-specific transporter) to inhibit creatine import. Decreased creatine levels can reduce ATP production and impair CD8+ T cell immune function, leading to immune escape by leukemic cells. In summary, leukemic cell-derived sEV-related miR-19a-3p confers immunosuppression to CD8+ T cells by targeting SLC6A8-mediated creatine import, indicating that sEV-related miR-19a-3p might be a promising therapeutic target for NPM1-mutated AML.

Tumour-derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8-mediated creatine import in NPM1-mutated acute myeloid leukaemia.

Mammalian poly A-binding proteins (PABPs) are highly conserved multifunctional RNA-binding proteins primarily involved in the regulation of mRNA translation and stability, of which PABPC1 is considered a central regulator of cytoplasmic mRNA homing and is involved in a wide range of physiological and pathological processes by regulating almost every aspect of RNA metabolism. Alterations in its expression and function disrupt intra-tissue homeostasis and contribute to the development of various tumors. There is increasing evidence that PABPC1 is aberrantly expressed in a variety of tumor tissues and cancers such as lung, gastric, breast, liver, and esophageal cancers, and PABPC1 might be used as a potential biomarker for tumor diagnosis, treatment, and clinical application in the future. In this paper, we review the abnormal expression, functional role, and molecular mechanism of PABPC1 in tumorigenesis and provide directions for further understanding the regulatory role of PABPC1 in tumor cells.

/pdf/pabpc1-mrna-stability-protein-translation-and-tumorigenesis-1gww9nsr.pdf

PABPC1——mRNA stability, protein translation and tumorigenesis

Tumor cells actively incorporate molecules (e.g., proteins, lipids, RNA) into particles named extracellular vesicles (EVs). Several groups have demonstrated that EVs can be transferred to target (recipient) cells, making EVs an important means of intercellular communication. Indeed, EVs are able to modulate the functions of target cells by reprogramming signaling pathways. In a cancer context, EVs promote the formation of a supportive tumor microenvironment (TME) and (pre)metastatic niches. Recent studies have revealed that immune cells, tumor cells and their secretome, including EVs, promote changes in the TME and immunosuppressive functions of immune cells (e.g., natural killer, dendritic cells, T and B cells, monocytes, macrophages) that allow tumor cells to establish and propagate. Despite the growing knowledge on EVs and on their roles in cancer and as modulators of the immune response/escape, the translation into clinical practice remains in its early stages, hence requiring improved translational research in the EVs field. Here, we comprehensively review the current knowledge and most recent research on the roles of EVs in tumor immune evasion and immunosuppression in both solid tumors and hematological malignancies. We also highlight the clinical utility of EV-mediated immunosuppression targeting and EV-engineering. Importantly, we discuss the controversial role of EVs in cancer biology, current limitations and future perspectives to further the EV knowledge into clinical practice.

/pdf/extracellular-vesicles-and-their-roles-in-the-tumor-immune-20fl0neb.pdf

Extracellular Vesicles and Their Roles in the Tumor Immune Microenvironment

Abstract The immune system in humans is a defense department against both exogenous and endogenous hazards, where CD8 + T cells play a crucial role in opposing pathological threats. Various immunotherapies based on CD8 + T cells have emerged in recent decades, showing their promising results in treating intractable diseases. However, in the fight against the constantly changing and evolving cancers, the formation and function of CD8 + T cells can be challenged by tumors that might train a group of accomplices to resist the T cell killing. As cancer therapy stepped into the era of immunotherapy, understanding the physiological role of CD8 + T cells, studying the machinery of tumor immune escape, and thereby formulating different therapeutic strategies become the imperative missions for clinical and translational researchers to fulfill. After brief basics of CD8 + T cell-based biology is covered, this review delineates the mechanisms of tumor immune escape and discusses different cancer immunotherapy regimens with their own advantages and setbacks, embracing challenges and perspectives in near future. 

CD8+ T cell-based cancer immunotherapy

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Tumour-derived small extracellular vesicles suppress CD8+ T cell immune function by inhibiting SLC6A8-mediated creatine import in NPM1-mutated acute myeloid leukaemia.