Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review

Abstract

Pancreatic cancer is an extremely malignant tumor with the lowest 5-year survival rate among all tumors. Pancreatic ductal adenocarcinoma (PDAC), as the most common pathological subtype of pancreatic cancer, usually has poor therapeutic results. Immune checkpoint inhibitors (ICIs) can relieve failure of the tumor-killing effect of immune effector cells caused by immune checkpoints. Therefore, they have been used as a novel treatment for many solid tumors. However, PDAC is not sensitive to monotherapy with ICIs, which might be related to the inhibitory immune microenvironment of pancreatic cancer. Therefore, the way to improve the microenvironment has raised a heated discussion in recent years. Here, we elaborate on the relationship between different immune cellular components in this environment, list some current preclinical or clinical attempts to enhance the efficacy of ICIs by targeting the inhibitory tumor microenvironment of PDAC or in combination with other therapies. Such information offers a better understanding of the sophisticated tumor-microenvironment interactions, also providing insights on therapeutic guidance of PDAC targeting.

The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis

“…Firstly, immunotherapy may be preferable over non-immunotherapy for NSCLC patients with BMs, with longer PFS (HR = 0.48) and OS (HR = 0.64). The advantage may be caused by the synergy between immunotherapy and chemotherapy/radiotherapy ( 81 – 86 ). For example, immunotherapy enhanced the radiotherapy-induced abscopal effect and reversed the immunosuppressive effect of radiation, by blocking the immune checkpoint between antigen-presenting cells and lymphocytes in regional lymph nodes and other organs.…”

Nanoparticle-based immunotherapy of pancreatic cancer

“…Since the discovery of NCRs, many of these ICIs such as ipilimumab and tremelimumab (CTLA4 inhibitors), durvalumab and atezolizumab (PD-L1 inhibitors) as well as pembrolizumab and nivolumab (PD-1 inhibitors) have been successfully applied in the treatment of solid tumors ( Chi et al, 2020 ; Principe et al, 2021 ). Monotherapeutic application of these checkpoint inhibitors in PC, however, did not show any promising results in clinical studies thus far ( Li et al, 2021 ). Other clinical trials in phase I/II with atezolizumab in combination with other drugs are currently recruiting patients (NCT03829501 and NCT04820179) ( Schizas et al, 2020 ).…”

“…Other clinical trials in phase I/II with atezolizumab in combination with other drugs are currently recruiting patients (NCT03829501 and NCT04820179) ( Schizas et al, 2020 ). Furthermore, there is increasing research on other NCR molecules including the V-domain Ig-containing suppressor of T-cell activation (VISTA), lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing-3 (TIM 3) ( Li et al, 2021 ). LAG-3 is expressed primarily on NK cells, B cells, CD4 + , and CD8 + T cells, where it blocks T cell receptor signaling by binding with high affinity to MHC class II molecules, thereby decreasing anti-tumor T cell activity.…”

“…LAG-3 is expressed primarily on NK cells, B cells, CD4 + , and CD8 + T cells, where it blocks T cell receptor signaling by binding with high affinity to MHC class II molecules, thereby decreasing anti-tumor T cell activity. LAG-3 has been found to be expressed on tumor-infiltrating T cells in PC, and its expression is associated with poor disease outcomes Consequently, clinical studies are investigating the inhibitory effect of LAG-3 in solid cancers ( Maruhashi et al, 2020 ; Li et al, 2021 ; Seifert et al, 2021 ).…”

Histone Deacetylase Inhibitors Restore Cancer Cell Sensitivity towards T Lymphocytes Mediated Cytotoxicity in Pancreatic Cancer

“…However, immunotherapy has shown to be less effective for PDAC treatment. In fact, PDAC cells can escape from immune recognition and CTL-mediated cytotoxicity through various tumour intrinsic and extrinsic mechanisms, including the loss of immunogenic tumour antigens, non-immunogenic behaviour of tumours due to their poor antigenicity, and formation of highly immunosuppressive tumour microenvironment (TME) [ 7 , 12 ]. Therefore, there is an urgent need to uncover the in-depth pathophysiology behind pancreatic cancer and, thus, to design effective therapeutic strategies to improve the prognosis of PDAC.…”