Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer

Yousuf, Suhail; Qiu, Mengjie; Voithenberg, Lena Voith von; Hulkkonen, Johannes; Macinkovic, Igor; Schulz, Axel; Hartmann, Domenic; Mueller, Florian; Mijatović, M; Ibberson, David; Al-Halabi, Karam; Hetzer, Jenny; Anders, Simon; Brüne, Bernhard; Mei, Henrik E.; Imbusch, Charles D.; Brors, Benedikt; Heikenwälder, Mathias; Gaida, Matthias M.; Büchler, Markus W.; Weigert, Andreas; Hackert, Thilo; Roth, Susanne

doi:10.1053/j.gastro.2023.05.036

Cited by 14 publications

(10 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The vast majority of CD4 (95%) and CD8 (88%) T cells in Untreated tumors exhibited transcriptomic signatures of Exhaustion (red population), Regulatory (CD4; purple population), or Naïve (blue population) ( Figure 3A and B respectively) T cells. These results are in accordance with clinical PDAC data where most intratumoral T cells are dysfunctional and have an impaired ability to respond adequately against the tumor [20]. Although each monotherapy reduced the Naïve and Exhausted populations and increased the Intermediate subsets, SBRT/IL-12mRNA resulted in the noted disappearance of Exhausted/Naïve/Regulatory T cells and a significant expansion of the Activated/Cycling and Intermediate CD4 and CD8 T cell populations ( Figure 3A and B ; note loss of red cells and increase of green and gold populations).…”

Section: Resultssupporting

confidence: 91%

Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer

Hughson,

Hannon,

Salama

et al. 2023

Preprint

View full text Add to dashboard Cite

The immunosuppressive milieu in pancreatic cancer (PC) is a significant hurdle to treatments, resulting in survival statistics that have barely changed in 5 decades. Here we present a combination treatment consisting of stereotactic body radiation therapy (SBRT) and IL-12 mRNA lipid nanoparticles delivered directly to pancreatic murine tumors. This treatment was effective against primary and metastatic models, achieving cures in both settings. IL-12 protein concentrations were transient and localized primarily to the tumor. Depleting CD4 and CD8 T cells abrogated treatment efficacy, confirming they were essential to treatment response. Single cell RNA sequencing from SBRT/IL-12 mRNA treated tumors demonstrated not only a complete loss of T cell exhaustion, but also an abundance of highly proliferative and effector T cell subtypes. SBRT elicited T cell receptor clonal expansion, whereas IL-12 licensed these cells with effector function. This is the first report demonstrating the utility of SBRT and IL-12 mRNA in PC.Statement of significanceThis study demonstrates the use of a novel combination treatment consisting of radiation and immunotherapy in murine pancreatic tumors. This treatment could effectively treat local and metastatic disease, suggesting it may have the potential to treat a cancer that has not seen a meaningful increase in survival in 5 decades.

show abstract

Section: Resultssupporting

confidence: 91%

Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer

Hughson,

Hannon,

Salama

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Intriguingly, the CD8 + T cells located within the lymphocyte enrichment region showed an altered spatial behavior. The spatial location and presence of CD8 + T cells is pivotal to the anti-tumor immunity response to PDAC [5,32,33]. Some components, such as myeloid cells and desmoplastic components in the TME, have been reported to impact the distribution of CD8 + T cells, while the role of local communication patterns around CD8 + T cells has yet to be defined [17][18][19]22,34].The proximity of CD8 + T cells to tumor cells has been well known to facilitate the recognition of tumor-associated antigens and subsequent tumor eradication [1][2][3][4][5].To assess the proximity of CD8 + T cells to tumor cells, we examined the distance from CD8 + T cells to their nearest tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Identifying the Spatial Architecture That Restricts the Proximity of CD8+ T Cells to Tumor Cells in Pancreatic Ductal Adenocarcinoma

Xia,

Ma,

Yang

et al. 2024

Cancers

View full text Add to dashboard Cite

The anti-tumor function of CD8+ T cells is dependent on their proximity to tumor cells. Current studies have focused on the infiltration level of CD8+ T cells in the tumor microenvironment, while further spatial information, such as spatial localization and inter-cellular communication, have not been defined. In this study, co-detection by indexing (CODEX) was designed to characterize PDAC tissue regions with seven protein markers in order to identify the spatial architecture that regulates CD8+ T cells in human pancreatic ductal adenocarcinoma (PDAC). The cellular neighborhood algorithm was used to identify a total of six conserved and distinct cellular neighborhoods. Among these, one unique spatial architecture of CD8+ T and CD4+ T cell-enriched neighborhoods enriched the majority of CD8+ T cells, but heralded a poor prognosis. The proximity analysis revealed that the CD8+ T cells in this spatial architecture were significantly closer to themselves and the CD4+ T cells than to the tumor cells. Collectively, we identified a unique spatial architecture that restricted the proximity of CD8+ T cells to tumor cells in the tumor microenvironment, indicating a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner and providing new insights into the biology of PDAC.

show abstract

“…57 The combination of scRNA-seq and spatial transcriptomics reveals the presence of unique immune subsets that may have been previously disregarded in the context of PDAC, as these subsets diverged from immune populations found in neighboring normal regions. 58 The utilization of scRNA-seq analysis has provided insights into the crucial role of neutrophils in innate immunity, as they actively contribute to tumor progression by participating in various processes such as cell proliferation, angiogenesis, tissue remodeling, immunosuppression, and metastasis. 59…”

Section: Single-cell Analysismentioning

confidence: 99%

Pancreatic cancer environment: from patient-derived models to single-cell omics

Gu,

Li,

Qiu

et al. 2024

Mol. Omics

View full text Add to dashboard Cite

show abstract

Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer

Cited by 14 publications

References 71 publications

Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer

Local Delivery of SBRT and IL12 by mRNA Technology Overcomes Immunosuppressive Barriers to Eliminate Pancreatic Cancer

Identifying the Spatial Architecture That Restricts the Proximity of CD8+ T Cells to Tumor Cells in Pancreatic Ductal Adenocarcinoma

Pancreatic cancer environment: from patient-derived models to single-cell omics

Contact Info

Product

Resources

About