Pancreatic Ductal Adenocarcinoma Contains an Effector and Regulatory Immune Cell Infiltrate that Is Altered by Multimodal Neoadjuvant Treatment

Abstract

ObjectiveThe immune response to pancreatic ductal adenocarcinoma (PDA) may play a role in defining its uniquely aggressive biology; therefore, we sought to clearly define the adaptive immune infiltrate in PDA.DesignWe used immunohistochemistry and flow cytometry to characterize the immune infiltrate in human PDA and compared our findings to the patients’ peripheral blood.ResultsIn contrast to the myeloid cell predominant infiltrate seen in murine models, T cells comprised the majority of the hematopoietic cell component of the tumor stroma in human PDA. Most intratumoral CD8+ T cells exhibited an antigen-experienced effector memory cell phenotype and were capable of producing IFN-γ. CD4+ regulatory T cells (Treg) and IL-17 producing T helper cells were significantly more prevalent in tumor than in blood. Consistent with the association with reduced survival in previous studies, we observed higher frequencies of both myeloid cells and Treg in poorly differentiated tumors. The majority of intratumoral T cells expressed the co-inhibitory receptor programmed death-1 (PD-1), suggesting one potential mechanism through which PDA may evade antitumor immunity. Successful multimodal neoadjuvant therapy altered the immunoregulatory balance and was associated with reduced infiltration of both myeloid cells and Treg.ConclusionOur data show that human PDA contains a complex mixture of inflammatory and regulatory immune cells, and that neoadjuvant therapy attenuates the infiltration of intratumoral cells associated with immunosuppression and worsened survival.

FOXP3 autoantibody as a potential early prognostic serum biomarker in patients with cervical cancer

“…An increased proportion of CD4 + CD25 + Tregs in peripheral lymphocytes and tumor-infiltrating lymphocytes was first demonstrated in patients with breast, ovarian, and pancreatic cancers and skin squamous cell carcinoma [24][25][26][27][28].…”

“…The underlying mechanism may be that the population of Tregs is higher in cancer patients than in healthy subjects because Tregs are involved in functional regulation of immune suppression and cancer patients are in an immunosuppressed state, and as FOXP3 is a specific marker of Tregs, it is therefore highly expressed in Tregs. Since then, many researchers have found the expression level of FOXP3 + Tregs is also increased in peripheral lymphocytes and tumor-infiltrating lymphocytes of patients with various malignant tumors such as epithelial malignant lesions, head and neck cancer, hepatocellular carcinoma, pancreatic cancer and breast cancer [25][26][27][28][29][30], suggesting that the expression level of FOXP3 + Tregs is closely related with tumor occurrence, development and prognosis. Upregulation of FOXP3 + Tregs in vivo is a common phenomenon in patients with malignant tumors.…”

Genetics and biology of pancreatic ductal adenocarcinoma

“…The number of T reg cells in the tumor correlates positively with advancing histological grade and increased lymph node metastasis (Jiang et al 2014). In addition, increased levels of T reg cells and MDSCs are associated with more poorly differentiated tumors (Shibuya et al 2014). A number of factors attract, convert, and expand T reg cells in the tumor microenvironment.…”

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

“…Intratumoural T-cell dysfunction is characterised by upregulation of inhibitory receptors, termed immune checkpoints, such as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene-3 and programmed death receptor-1 (PD-1). Recently, it was described that the majority of the intratumoural T cells of patients with pancreatic cancer expressed the co-inhibitory checkpoint receptor PD-1 99. As a result, successful antitumour T-cell responses are compromised.…”