New immune map uncovers key pancreatic cancer insights

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Feb 12 2025

A study unveils a newly constructed immune map, highlighting the distinct immune infiltrate patterns in pancreatic tumors. These findings could pave the way for tailored immunotherapies and improved treatment strategies for pancreatic cancer patients.

Study: Distinct Immune Cell Infiltration Patterns in Pancreatic Ductal Adenocarcinoma (PDAC) Exhibit Divergent Immune Cell Selection and Immunosuppressive Mechanisms. Image Credit: Shutterstock AI Generator / Shutterstock.com

A recent Nature Communications study determines a complex immune infiltrate pattern based on a newly constructed immune map developed using pancreatic cancer cells.

The complex microenvironment of pancreatic tumors

Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of less than 10%, thus making PDAC the most lethal type of cancer. About 15% of PDAC patients benefit from surgical resection; however, most patients with PDAC are treated with chemotherapy and between 0.5-1% will receive immunotherapy. Despite their availability, there remains an urgent need to develop more effective treatments for PDAC to improve patient outcomes.

Numerous studies have investigated the microenvironment surrounding PDAC tumors, with T-cells often identified as the dominant immune cell type. For example, the researchers of the current study previously identified tumor-infiltration lymphocytes (TILs) in PDAC tumors, including limited exhaustion of a subset of CD8 T-cells, a significant number of senscent CD4 and CD8 T-cells, as well as activated T-regulatory (Treg) cells expressing various checkpoints that reflect an immunosuppressive tumor microenvironment (TME).

However, there remains a lack of data on the clonal evolution and differentiation pathways involved in the PDAC TME. Investigating the clonal distribution and evolution of both T- and B-cells is crucial, as the migration of these cells between draining lymph nodes and the tumor can be manipulated to devise effective and sustained anti-tumoral immune responses.

About the study

The aim of the current study was to explore the key features of adaptive immune responses in PDAC tumors with high levels of myeloid and adaptive cell populations. Moreover, the researchers were interested in identifying specific immune suppression pathways that can be used to distinguish myeloid- and adaptive-high patients.

The PancrImmune dataset consisted of single cell ribonucleic acid (RNA) sequencing (scRNA-seq), Antibody-Derived Tags sequencing (ADT-seq), as well as B-cell receptor (BCR) and T-cell receptor (TCR) sequencing on CD45+ cells obtained from 12 treatment-naïve patients and matched peripheral blood mononuclear cells (PBMCs). Existing PDAC scRNA-seq datasets from Peng and Steele were also analyzed and used as a reference for PancrImmune data.

To identify pathways to be targeted for improving immune cell trafficking, the nature and determinants of B- and T-cell immunosurveillance in PDAC were investigated. These findings were validated at the protein level using samples from the Adjuvant Pancreatic Cancer Trial (APACT), which is an international phase III clinical trial of adjuvant chemotherapy.

Several bioinformatics tools including scClonetoire, SVMCellTransfer, and scRepTransition were developed to quantify clonality, annotate scRNAseq datasets, as well as capture the clonal overlap between B- or T-cell subsets, respectively. These efforts led to the development of a valuable scMulti-omics dataset that offers novel insights into the PDAC TME.

Study findings

Patient samples were categorized as ‘adaptive-enriched’ if high B- and T-cell tumor infiltrate proportions were present, whereas myeloid-enriched (ME) tumors exhibietd high myeloid proportions accompanied by low levels of B- and T-cells. When AE and ME patients were compared, AE tumors exhibited higher levels of T follicular helper (fh), naïve CD4 cells, and CD8 effector memory cells, which suggests the presence of an inter-relationship between B- and T-cells in PDAC.

Comparatively, ME tumors exhibited higher proportions of T regulatory (Treg) cells, activated Treg, and gamma-delta (gd) T-cells. Thus,s the ME tumor microenvironment may be more immunosuppressive than AE tumors. Other notable characteristics of AE tumors include dysfunctional germinal center responses, lower isotype switching, higher occurrence of immunoglobulin M (IgM)-positive B-cells, and lower levels of plasma cells. The reduced survival signatures associated with PDAC ME tumors may be attributed to the lower levels of CD8+ T-cell infiltration into tumors and high CD163+ macrophage levels.

Several mechanisms may be involved in the reduced germinal center B-cell response in ME tumors, some of which include macrophage-plasma cell crosstalk that leads to the differentiation of plasma cell T follicular regulatory cells, which further inhibits germinal center B-cell responses. The low levels of crucial chemokine receptors may also prevent B- and T-cell trafficking into tissues that would otherwise facilitate adaptive cell functions.

Notably, all of the observed differences between AE and ME tumors were independent of patient factors including gender, age, prior disease history, or diabetes status.

Conclusions

PDAC patients with greater adaptive immune responses exhibited a highly distinct B- and T-cell clonal selection, diversification, and differentiation. These observations may be used in the future to tailor specific treatments for PDAC, as patients with higher myeloid infiltration may benefit from selectively targeting Treg functions. Comparatively, PDAC tumors with a greater infiltration of adaptive cells may respond better to immunotherapies that target dysfunctional tertiary lymphoid structures (TLSs).

We demonstrate the need for trials to assess changes in immune infiltration over time between different therapies to build a spatio-temporal understanding of the tumor-immune cross-talk dynamics.”