Specialty (if any): Surgical Oncology

Keywords: Pancreatic ductal adenocarcinoma (PDAC), Immune checkpoint inhibitors (ICIs), lymphoid aggregates

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a dismal 5-year survival rate of 13%. Immune checkpoint inhibitors (ICIs) have limited efficacy in metastatic PDAC due to its immunosuppressive tumor microenvironment and barriers to immune cell infiltration. Most clinical trials evaluating ICIs focused on advanced disease.

Objective: We conducted a preoperative trial of PD-1 inhibition in early-stage PDAC to assess its efficacy and characterize immune cell changes in resected tumors.

Methods: In a single-arm, phase I/II trial, we investigated the immune-related effects of FOLFIRINOX (FFX) with PD-1 inhibition (nivolumab) in patients with borderline-resectable PDAC. Tumor infiltrating leukocytes were characterized with bulk RNA sequencing of tumor specimens with CIBERSORT deconvolution. Lymphoid aggregates (LAs) were evaluated by immunohistochemistry (IHC). Functional phenotypes of LA cell populations were defined by Xenium 5K Prime spatial transcriptomics on nine patient tumors.

Results: Twenty-eight patients were enrolled and received FFX+nivolumab, with a median survival of 33 months. Twenty-two proceeded to surgical resection. Patients with high intra-tumoral plasma cells and normal CA19-9 had longer survival (HR:0.22, P=0.045). Bulk RNA sequencing revealed an increase in intra-tumoral plasma cell abundance with PD-1 inhibition. IHC identified more than 400 LAs across all samples, with LA density – rather than B cell density – predicting intra-tumoral plasma cells. Spatial transcriptomics demonstrated that LAs were enriched with plasma cells at the expense of B cells, and the plasma cell-to-B cell ratio (PBR) correlated with proliferating T cells.

Conclusions: In borderline-resectable PDAC, PD-1 inhibition plus FOLFIRINOX did not improve survival compared to FOLFIRINOX alone, mirroring findings in advanced disease. However, PD-1 inhibition increased intra-tumoral plasma cells, which correlated with LA density and immune activation. Patients with high plasma cells and low tumor burden had significantly longer survival. While PD-1 inhibition induces immune changes, efficacy remains limited, highlighting the need to investigate other factors contributing to immune evasion in PDAC.

Specialty (if any): Surgical Oncology

Keywords: Pancreatic ductal adenocarcinoma (PDAC), Immune checkpoint inhibitors (ICIs), lymphoid aggregates

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a dismal 5-year survival rate of 13%. Immune checkpoint inhibitors (ICIs) have limited efficacy in metastatic PDAC due to its immunosuppressive tumor microenvironment and barriers to immune cell infiltration. Most clinical trials evaluating ICIs focused on advanced disease.

Objective: We conducted a preoperative trial of PD-1 inhibition in early-stage PDAC to assess its efficacy and characterize immune cell changes in resected tumors.

Methods: In a single-arm, phase I/II trial, we investigated the immune-related effects of FOLFIRINOX (FFX) with PD-1 inhibition (nivolumab) in patients with borderline-resectable PDAC. Tumor infiltrating leukocytes were characterized with bulk RNA sequencing of tumor specimens with CIBERSORT deconvolution. Lymphoid aggregates (LAs) were evaluated by immunohistochemistry (IHC). Functional phenotypes of LA cell populations were defined by Xenium 5K Prime spatial transcriptomics on nine patient tumors.

Results: Twenty-eight patients were enrolled and received FFX+nivolumab, with a median survival of 33 months. Twenty-two proceeded to surgical resection. Patients with high intra-tumoral plasma cells and normal CA19-9 had longer survival (HR:0.22, P=0.045). Bulk RNA sequencing revealed an increase in intra-tumoral plasma cell abundance with PD-1 inhibition. IHC identified more than 400 LAs across all samples, with LA density – rather than B cell density – predicting intra-tumoral plasma cells. Spatial transcriptomics demonstrated that LAs were enriched with plasma cells at the expense of B cells, and the plasma cell-to-B cell ratio (PBR) correlated with proliferating T cells.

Conclusions: In borderline-resectable PDAC, PD-1 inhibition plus FOLFIRINOX did not improve survival compared to FOLFIRINOX alone, mirroring findings in advanced disease. However, PD-1 inhibition increased intra-tumoral plasma cells, which correlated with LA density and immune activation. Patients with high plasma cells and low tumor burden had significantly longer survival. While PD-1 inhibition induces immune changes, efficacy remains limited, highlighting the need to investigate other factors contributing to immune evasion in PDAC.