PD-1+CD8+ T Cells Proximal to PD-L1+CD68+ Macrophages Are Associated with Poor Prognosis in Pancreatic Ductal Adenocarcinoma Patients

Yang, Xiaobao; Wang, Guanzheng; Song, Yue; Zhuang, Tongtao; Li, Yifei; Xie, Yujie; Fei, Xuefeng; Xu, Dakang; Hu, Yiqun

doi:10.3390/cancers15051389

Cited by 2 publications

References 32 publications

(33 reference statements)

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Spatial Single-Cell Transcriptomic Analysis in Breast Cancer Reveals Potential Biomarkers for PD-1 Blockade Therapy

Wang,

Song,

Hong

et al. 2024

Preprint

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Introduction: Spatially defined cellular interaction and crosstalk are eminently important in deciphering key molecular messages driving oncogenesis and disease progression. To date, methods enabling high-plex true single-cell resolution profiling under spatial settings are gradually becoming available and those majorly include the expansion of spatial transcriptomics (ST) being utilized. Results: Through in-depth spatial single-cell profiling on four breast cancer (BC) tissue samples bearing distinct biological characteristics, we evaluated the analytical performance benchmarked against conventional pathology and by selecting pre-defined region-of-interests (ROIs), we consolidated the technical robustness of this method in defining different molecular subtypes at the transcript level matching with canonical immunohistochemistry. Moreover, we demonstrated that high-dimensional ST data is capable of identifying a major cellular network inter-wired via macrophage and cytotoxic T cells interaction in tumor adjacent cellular neighborhood via PD-L1/CD80 and CD86/CTLA4 axis, a phenomenon reflecting an improved PD-1 mediated drug response observed clinically. By incorporating open-source computational methods (Tangram and SpaGE), we found compatible inference tools for in-situ expression imputation, an approach generalizable to enable deeper spatial profiling using Xenium in-situ or other parallel approaches. Discussion: Our spatial single-cell ST sets as a technical and analytical prototype for those using similar approaches for high-dimensional in-situ profiling work. Materials: We applied a newly developed spatial single-cell technology (Xenium in-situ) to interrogate the spatial single-cell architecture of the complex tumor microenvironment on a set of breast cancer patient tissues (luminal-type, HER2 2+/HR- and triple negative breast cancer, TNBC) and benchmarked against multiple clinicopathological features using bioinformatic tools.

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Spatial Single-Cell Transcriptomic Analysis in Breast Cancer Reveals Potential Biomarkers for PD-1 Blockade Therapy

Wang,

Song,

Hong

et al. 2024

Preprint

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New avenues for the treatment of immunotherapy-resistant pancreatic cancer

Silva,

Lemos,

Luz

et al. 2024

World J Gastrointest Oncol

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Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53 , and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.

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PD-1+CD8+ T Cells Proximal to PD-L1+CD68+ Macrophages Are Associated with Poor Prognosis in Pancreatic Ductal Adenocarcinoma Patients

Cited by 2 publications

References 32 publications

Spatial Single-Cell Transcriptomic Analysis in Breast Cancer Reveals Potential Biomarkers for PD-1 Blockade Therapy

Spatial Single-Cell Transcriptomic Analysis in Breast Cancer Reveals Potential Biomarkers for PD-1 Blockade Therapy

New avenues for the treatment of immunotherapy-resistant pancreatic cancer

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