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The Exocrine Pancreas.

The clinical responses observed following treatment with immune checkpoint inhibitors (ICIs) support immunotherapy as a potential anticancer treatment. However, a large proportion of patients cannot benefit from it due to resistance or relapse, which is most likely attributable to the multiple immunosuppressive cells in the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs), a heterogeneous array of pathologically activated immature cells, are a chief component of immunosuppressive networks. These cells potently suppress T-cell activity and thus contribute to the immune escape of malignant tumors. New findings indicate that targeting MDSCs might be an alternative and promising target for immunotherapy, reshaping the immunosuppressive microenvironment and enhancing the efficacy of cancer immunotherapy. In this review, we focus primarily on the classification and inhibitory function of MDSCs and the crosstalk between MDSCs and other myeloid cells. We also briefly summarize the latest approaches to therapies targeting MDSCs. 

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Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy

The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy. 

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Reshaping the systemic tumor immune environment (STIE) and tumor immune microenvironment (TIME) to enhance immunotherapy efficacy in solid tumors

Bulk sequencing methodologies have allowed us to make great progress in cancer research. Unfortunately, these techniques lack the resolution to fully unravel the epigenetic mechanisms that govern tumor heterogeneity. Consequently, many novel single cell-sequencing methodologies have been developed over the past decade, allowing us to explore the epigenetic components that regulate different aspects of cancer heterogeneity, namely: clonal heterogeneity, tumor microenvironment (TME), spatial organization, intratumoral differentiation programs, metastasis, and resistance mechanisms. In this review, we explore the different sequencing techniques that enable researchers to study different aspects of epigenetics (DNA methylation, chromatin accessibility, histone modifications, DNA-protein interactions, and chromatin 3D architecture) at the single cell level, their potential applications in cancer, and their current technical limitations. 

Single cell cancer epigenetics.

Cancer-associated fibroblasts (CAFs) comprise the majority of the tumor bulk of pancreatic ductal adenocarcinomas (PDACs). Current efforts to eradicate these tumors focus predominantly on targeting the proliferation of rapidly growing cancer epithelial cells. We know that this is largely ineffective with resistance arising in most tumors following exposure to chemotherapy. Despite the long-standing recognition of the prominence of CAFs in PDAC, the effect of chemotherapy on CAFs and how they may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that CAFs exposed to chemotherapy have an active role in regulating the survival and proliferation of cancer cells. We found that CAFs are intrinsically resistant to gemcitabine, the chemotherapeutic standard of care for PDAC. Further, CAFs exposed to gemcitabine significantly increase the release of extracellular vesicles called exosomes. These exosomes increased chemoresistance-inducing factor, Snail, in recipient epithelial cells and promote proliferation and drug resistance. Finally, treatment of gemcitabine-exposed CAFs with an inhibitor of exosome release, GW4869, significantly reduces survival in co-cultured epithelial cells, signifying an important role of CAF exosomes in chemotherapeutic drug resistance. Collectively, these findings show the potential for exosome inhibitors as treatment options alongside chemotherapy for overcoming PDAC chemoresistance.

Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells

Single-cell sequencing, including genomics, transcriptomics, epigenomics, proteomics and metabolomics sequencing, is a powerful tool to decipher the cellular and molecular landscape at a single-cell resolution, unlike bulk sequencing, which provides averaged data. The use of single-cell sequencing in cancer research has revolutionized our understanding of the biological characteristics and dynamics within cancer lesions. In this review, we summarize emerging single-cell sequencing technologies and recent cancer research progress obtained by single-cell sequencing, including information related to the landscapes of malignant cells and immune cells, tumor heterogeneity, circulating tumor cells and the underlying mechanisms of tumor biological behaviors. Overall, the prospects of single-cell sequencing in facilitating diagnosis, targeted therapy and prognostic prediction among a spectrum of tumors are bright. In the near future, advances in single-cell sequencing will undoubtedly improve our understanding of the biological characteristics of tumors and highlight potential precise therapeutic targets for patients.

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Applications of single-cell sequencing in cancer research: progress and perspectives

As the most important component of the stromal cell population in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are crucial players in tumor initiation and progression. The interaction between CAFs and tumor cells, as well as the resulting effect, is much greater than initially expected. Numerous studies have shown that noncoding RNAs (ncRNAs) play an irreplaceable role in this interplay, and related evidence continues to emerge and advance. Under the action of ncRNAs, normal fibroblasts are directly or indirectly activated into CAFs, and their metabolic characteristics are changed; thus, CAFs can more effectively promote tumor progression. Moreover, via ncRNAs, activated CAFs can affect the gene expression and secretory characteristics of cells, alter the TME and enhance malignant biological processes in tumor cells to contribute to tumor promotion. Previously, ncRNA dysregulation was considered the main mechanism by which ncRNAs participate in the crosstalk between CAFs and tumor cells. Recently, however, exosomes containing ncRNAs have been identified as another vital mode of interaction between these two types of cells, with a more direct and clear function. Gaining an in-depth understanding of ncRNAs in CAFs and the complex regulatory network connecting CAFs with tumor cells might help us to establish more effective and safer approaches for cancer therapies targeting ncRNAs and CAFs and offer new hope for cancer patients.

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The promising role of noncoding RNAs in cancer-associated fibroblasts: an overview of current status and future perspectives.

Development and multicenter validation of a nomogram for preoperative prediction of lymph node positivity in pancreatic cancer (NeoPangram)

Background The benefits of neoadjuvant chemotherapy (NCT) in pancreatic cancer (PC) have been realized and gradually accepted. FOLFIRINOX and gemcitabine and nab-paclitaxel (GA) are the two most widely used regimens for PC NCT. Methods The literature was systematically reviewed by searching MEDLINE, EMBASE, Web of Science and the Cochrane Library for studies published until September 2020. Results Eight studies were eligible for the meta-analysis. Compared to GA, neoadjuvant FOLFIRINOX significantly prolonged overall survival [hazard ratio (HR) =0.65, 95% confidence interval (95% CI): 0.55-0.77; P<0.001]. FOLFIRINOX provided better survival benefits in the first three years after surgery; however, the 4- and 5-year survival probabilities of the two strategies were similar based on a conservative estimation in the random effect model. The perioperative parameters analysed included perineural invasion (PNI), lymphovascular invasion (LVSI), R0 status, postoperative complications and resection rate. The PNI rate was marginally elevated in the GA group compared with the FOLFIRINOX cohort [79.8% vs. 70.5%, odds ratio (OR) =0.70, 95% CI: 0.47-1.06, P=0.09], which may account for the potential survival benefits of FOLFIRINOX. Conclusions The results of our meta-analysis suggest that FOLFIRINOX is non-inferior to GA in patients who are FOLFIRINOCX capable.

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Head-to-head comparison between FOLFIRINOX and gemcitabine plus nab-paclitaxel in the neoadjuvant chemotherapy of localized pancreatic cancer: a systematic review and meta-analysis.

Wei Wang

Papers

Applications of single-cell sequencing in cancer research: progress and perspectives

The promising role of noncoding RNAs in cancer-associated fibroblasts: an overview of current status and future perspectives.

Development and multicenter validation of a nomogram for preoperative prediction of lymph node positivity in pancreatic cancer (NeoPangram)

Head-to-head comparison between FOLFIRINOX and gemcitabine plus nab-paclitaxel in the neoadjuvant chemotherapy of localized pancreatic cancer: a systematic review and meta-analysis.