Spatial genomics reveals a high number and specific location of B cells in the pancreatic ductal adenocarcinoma microenvironment of long-term survivors

Abstract

Background and aimOnly 10% of pancreatic ductal adenocarcinoma (PDAC) patients survive longer than five years. Factors underlining long-term survivorship in PDAC are not well understood. Therefore, we aimed to identify the key players in the tumor immune microenvironment (TIME) associated with long-term survivorship in PDAC patients.MethodsThe immune-related gene expression profiles of resected PDAC tumors of patients who survived and remained recurrence-free of disease for ≥36 months (long-term survivors, n=10) were compared to patients who had survived ≤6 months (short-term survivors, n=10) due to tumor recurrence. Validation was performed by the spatial protein expression profile of immune cells using the GeoMx™ Digital Spatial Profiler. An independent cohort of samples consisting of 12 long-term survivors and 10 short-term survivors, was used for additional validation. The independent validation was performed by combining qualitative immunohistochemistry and quantitative protein expression profiling.ResultsB cells were found to be significantly increased in the TIME of long-term survivors by gene expression profiling (p=0.018). The high tumor infiltration of B cells was confirmed by spatial protein profiling in the discovery and the validation cohorts (p=0.002 and p=0.01, respectively). The higher number of infiltrated B cells was found mainly in the stromal compartments of PDAC samples and was exclusively found within tumor cells in long-term survivors.ConclusionThis is the first comprehensive study that connects the immune landscape of gene expression profiles and protein spatial infiltration with the survivorship of PDAC patients. We found a higher number and a specific location of B cells in TIME of long-term survivors which emphasizes the importance of B cells and B cell-based therapy for future personalized immunotherapy in PDAC patients.

Single-cell immune multi-omics and repertoire analyses in pancreatic ductal adenocarcinoma reveal differential immunosuppressive mechanisms within different tumour microenvironments

“…However, the immune-incompetent TME is potentially preventing proper anti-tumour immune responses as can be seen with high levels of CXCR4 on the B cell compartment, potentially restricting their access to the tumour core via retention outside. Indeed, higher number and a specific locations of B cells quality in TME, maturity of TLSs, and neoantigen have been shown in PDAC long-term survivors 16 . These data suggest that patients with higher adaptive cell infiltration may benefit most from boosting the immune response against abortive or dysfunctional TLSs, which may potentially be achieved by cancer vaccines 57 , targeting T cell senescence and/or targeting chemokines.…”

“…PDAC has been traditionally considered to have a low mutation rate, suggesting a low prevalence of antigens to stimulate the immune response. However, seeing the presence of activated and exhausted cells within the TME, and associations between cytotoxic CD8 T cells, B cells and neoantigen quality with patient survival 16,17 suggests the presence of specific stimuli and warrants the investigation of the clonal distribution and evolution of both T and B cells. Multiple previous studies have shown that higher adaptive immune cell infiltration is associated with marginally better survival 8,18 , however, both adaptive and myeloid enriched PDAC patients have dismal prognosis 6 .…”

Neoadjuvant chemotherapy is associated with suppression of the B cell-centered immune landscape in pancreatic ductal adenocarcinoma

“…Based on the drastic effects of NeoTx on the immune landscape of PDAC, we further explored the differential association of lymphocyte frequencies with OS in NeoTx and PR patients. So far, contradictory results regarding the prognostic value of CD20 + B cells in PDAC have been published, with several studies describing a positive impact on survival ( 20 , 24 , 77 , 78 ), while one report observed a negative association ( 79 ). A meta-analysis integrating multiple studies reported no link between B cell frequencies and survival in PDAC ( 80 ).…”

Cellular collusion: cracking the code of immunosuppression and chemo resistance in PDAC

“…For instance, Breg - FcRγ + TAMs crosstalk drives a tumor-promoting macrophage phenotype supporting tumor growth ( 100 ). The spatial organization of immune cells within the TME influences survival and response to therapy in several tumor types, including PDAC ( 101 , 102 ). By comparing transcriptional data of PDAC tissue samples from resected long-term and short-term survivors, a higher infiltration of B cells was observed in long-term survivors.…”

“…By comparing transcriptional data of PDAC tissue samples from resected long-term and short-term survivors, a higher infiltration of B cells was observed in long-term survivors. Spatial data of long-term survivors revealed the proximity of CD20 + B cells and T cells with an activated effector phenotype, highlighting the importance of studying the differences in immune infiltration in a specific location ( 101 ).…”