Immunologic alterations in the pancreatic cancer microenvironment of patients treated with neoadjuvant chemotherapy and radiotherapy

Farren, Matthew R.; Sayegh, Layal; Ware, Michael B.; Chen, Hsiao-Rong; Gong, Junsong; Liang, Yan; Krasinskas, Alyssa M.; Maithel, Shishir K.; Zaidi, Mohammad Y.; Sarmiento, Juan M.; Kooby, David A.; Patel, Pretesh; El‐Rayes, Bassel F.; Shaib, Walid Labib; Lesinski, Gregory B.

doi:10.1172/jci.insight.130362

Cited by 45 publications

(52 citation statements)

References 31 publications

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“…Incorporating the PDAC-MGIC in nSolver ® Advanced Analysis software enabled discovering the effect of neoadjuvant therapy on the immune profiling of PDAC tissue samples. Our method showed the same effect of neoadjuvant therapy in PDAC samples as was reported before (41). However, it highlighted more clearly that the addition of a radiotherapy regimen to FOLFIRINOX induces more profound changes in gene expression than FOLFIRINOX alone.…”

Section: Identifying Immune Cells In Pdacsupporting

confidence: 77%

“…The clinical utility is demonstrated by uploading our defined marker genes PDAC-GMICs in the nSolver ® Advanced Analysis module to identify immune cells in the "cell type profiling" section. The PDAC-GMIC set was used to assess the composition of the immune microenvironment for all patients in GSE129492 (41). The abundance of the immune cell types is represented by a cell score, which is the average log2-transformed expression values of their corresponding marker genes.…”

Section: Utilization Of Pdac-mgicsmentioning

confidence: 99%

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Section: Identifying Immune Cells In Pdacsupporting

confidence: 77%

Section: Utilization Of Pdac-mgicsmentioning

confidence: 99%

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“… 76–78 In contrast, chemotherapy is hypothesized to increase T-cell priming, which we discuss further briefly, and data from our group and others indeed suggest immune changes elicited by chemotherapy are significant. 76 79 Thus, considering how immunotherapy approaches can be strategically combined with radiation or chemotherapy will be key in moving forward.…”

Section: Therapeutic Approaches To Ameliorate T-cell Exclusion and Inmentioning

confidence: 74%

“…Results from these studies indicate an influx in suppressive macrophages, Tregs and increases in inducible Nitic Oxide Synthase (iNOS) release by cancer-associated fibroblasts that together result in poor T-cell activity and sparse infiltration of pancreatic tumor tissues. [76][77][78] In contrast, chemotherapy is hypothesized to increase T-cell priming, which we discuss further briefly, and data from our group and others indeed suggest immune changes elicited by chemotherapy are significant. 76 79 Thus, considering how immunotherapy approaches can be strategically combined with radiation or chemotherapy will be key in moving forward.…”

Section: Therapeutic Approaches To Ameliorate T-cell Exclusion and Inmentioning

confidence: 76%

Mirage or long-awaited oasis: reinvigorating T-cell responses in pancreatic cancer

Ware

El‐Rayes

Lesinski

2020

J Immunother Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is plagued by a dismal 5-year survival rate, early onset of metastasis and limited efficacy of systemic therapies. This scenario highlights the need to fervently pursue novel therapeutic strategies to treat this disease. Recent research has uncovered complicated dynamics within the tumor microenvironment (TME) of PDAC. An abundant stroma provides a framework for interactions between cancer-associated fibroblasts, suppressive myeloid cells and regulatory lymphocytes, which together create an inhospitable environment for adaptive immune responses. This accounts for the poor infiltration and exhausted phenotypes of effector T cells within pancreatic tumors. Innovative studies in genetically engineered mouse models have established that with appropriate pharmacological modulation of suppressive elements in the TME, T cells can be prompted to regress pancreatic tumors. In light of this knowledge, innovative combinatorial strategies involving immunotherapy and targeted therapies working in concert are rapidly emerging. This review will highlight recent advances in the field related to immune suppression in PDAC, emerging preclinical data and rationale for ongoing immunotherapy clinical trials. In particular, we draw attention to foundational findings involving T-cell activity in PDAC and encourage development of novel therapeutics to improve T-cell responses in this challenging disease.

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“…Results of further analyses including unsupervised hierarchical clustering and PCA demonstrated that ROIs from the tumor, stroma/ immune cells, and normal epithelial cells were grouped into distinct clusters, indicating that the specific protein or RNA expression information from different cellular contexts on the slides was precisely captured. Though our demonstrative work is simple, many other sophisticated approaches of DSP usage have been demonstrated elsewhere [42,[51][52][53]. Several ROI selection strategies are available to suit various research needs such as global deep profiling for full tissue sections, segmentation mode for precise analysis between tissue compartments, and rare cell profiling mode [42].…”

Section: Discussionmentioning

confidence: 99%

Spatially-resolved proteomics and transcriptomics: An emerging digital spatial profiling approach for tumor microenvironment

Wang¹,

Wang²,

Zhang³

et al. 2021

Vis Cancer Med

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Digital spatial profiling (DSP) is an emerging powerful technology for proteomics and transcriptomics analyses in a spatially resolved manner for formalin-fixed paraffin-embedded (FFPE) samples developed by nanoString Technologies. DSP applies several advanced technologies, including high-throughput readout technologies (digital optical barcodes by nCounter instruments or next generation sequencing (NGS)), programmable digital micromirror device (DMD) technology, and microfluidic sampling technologies into traditional immunohistochemistry (IHC) and RNA in situ hybridization (ISH) approaches, creating an innovative tool for discovery, translational research, and clinical uses. Since its launch in 2019, DSP has been rapidly adopted, especially in immuno-oncology and tumor microenvironment research areas, and has revealed valuable information that was inaccessible before. In this article, we report the successful setup and validation of the first DSP technology platform in China. Both DSP spatial protein and RNA profiling approaches were validated using FFPE colorectal cancer tissues. Regions of interest (ROIs) were selected in the areas enriched with tumor cells, stroma/immune cells, or normal epithelial cells, and multiplex spatial profiling of both proteins and RNAs were performed. DSP spatial profiling data were processed and normalized accordingly, validating the high quality and consistency of the data. Unsupervised hierarchical clustering as well as principal component analysis (PCA) grouped tumor, stroma/immune cells, and normal epithelial cells into distinct clusters, indicating that the DSP approach effectively captured the spatially resolved proteomics and transcriptomics profiles of different compartments within the tumor microenvironment. In summary, the results confirmed the expected sensitivity and robustness of the DSP approach in profiling both proteins and RNAs in a spatially resolved manner. As a novel technology in highly complex spatial analyses, DSP endows refined analytical power from the tumor microenvironment perspective with the potential of scaling up to more analyzable targets at relatively low cell input levels. We expect that the DSP technology will greatly advance a wide range of biomedical research, especially in immuno-oncology and tumor microenvironment research areas.

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Immunologic alterations in the pancreatic cancer microenvironment of patients treated with neoadjuvant chemotherapy and radiotherapy

Cited by 45 publications

References 31 publications

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Mirage or long-awaited oasis: reinvigorating T-cell responses in pancreatic cancer

Spatially-resolved proteomics and transcriptomics: An emerging digital spatial profiling approach for tumor microenvironment

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