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Review
. 2024 Jun 4;17(1):40.
doi: 10.1186/s13045-024-01561-6.

Current and future immunotherapeutic approaches in pancreatic cancer treatment

Pooya Farhangnia  1   2   3   4 , Hossein Khorramdelazad  5 , Hamid Nickho  2   3 , Ali-Akbar Delbandi  6   7   8
Affiliations
Review

Current and future immunotherapeutic approaches in pancreatic cancer treatment

Pooya Farhangnia et al. J Hematol Oncol. .

Abstract

Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.

Keywords: Adoptive cell therapy; CAR NK cell therapy; CAR T-cell therapy; Cancer vaccine; Immune checkpoint blockade; Immune checkpoint inhibitor; Oncolytic virus therapy; Pancreatic cancer immunotherapy; Pancreatic ductal adenocarcinoma.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Tumor microenvironment (TME) in pancreatic cancer. ADCC: Antibody-dependent cellular cytotoxicity; APC: Antigen-presenting cell; CAF: Cancer-associated fibroblast; CTL: Cytotoxic T lymphocyte; DC: Dendritic cell; DLL: Delta like canonical notch ligand; ECM: Extracellular matrix; GM-CSF: Granulocyte–macrophage colony-stimulating factor; HGF: Hepatocyte growth factor; IDO: Indoleamine 2,3-dioxygenase; IFNs-I: Type I interferons; IFN-γ: Interferon-gamma; IL-2: Interleukin 2; MDSC: Myeloid-derived suppressor cell; MMP: Matrix metalloproteinase; MQ: Macrophage; MSC: Mesenchymal stromal cell; NK: Natural killer; NO: Nitric oxide; PCSC: Pancreatic cancer stem cell; PDAC: Pancreatic ductal adenocarcinoma; PDGF: Platelet-derived growth factor; PSC: Pancreatic stellate cell; STING: Stimulator of interferon genes; TAM: Tumor-associated macrophage; TAN: Tumor-associated neutrophil; TGF-β: Transforming growth factor beta; Th1: Type 1 T helper; TNF-α: Tumor necrosis factor alpha; Treg: Regulatory T cell; VEGF: Vascular endothelial growth factor
Fig. 2
Fig. 2
Crosstalk between pancreatic ductal adenocarcinoma (PDAC) cells and key components of tumor microenvironment (TME). Arg1: Arginase 1; BMPs: Bone morphogenetic proteins; Breg: Regulatory B cell; BTK: Bruton's tyrosine kinase; CAFs: Cancer-associated fibroblast; CSF1: Colony stimulating factor 1; CTGF: Connective tissue growth factor; DC: Dendritic cell; FAP: Fibroblast activation protein; HIF: Hypoxia-inducible factor; IDO: Indoleamine 2,3-dioxygenase; iNOS: Inducible nitric oxide synthase; LIF: Leukemia inhibitory factor; M-CSF: Macrophage colony-stimulating factor; MDSC: Myeloid-derived suppressor cell; MHC: Major histocompatibility complex; MSCs: Mesenchymal stem/stromal cells; NK: Natural killer; Pin1: Peptidylpropyl isomerase; ROS: Reactive oxygen species; SPP-1: Osteopontin/secreted phosphoprotein 1; TAM: Tumor-associated macrophage; TAN: Tumor-associated neutrophil; TCR: T cell receptor; TGF-β: Transforming growth factor beta; TIGIT: T cell immunoreceptor with Ig and ITIM domains; TNF: Tumor necrosis factor; Treg: Regulatory T cell; VEGF: Vascular endothelial growth factor
Fig. 3
Fig. 3
Immunotherapeutic strategies in pancreatic cancer treatment. The immune response to pancreatic ductal adenocarcinoma (PDAC) is guided by antigen-presenting machinery involving dendritic cells (DCs), inflammatory macrophages, and CD4+ helper T cells, leading to the activation of CD8+ cytotoxic T cells to eliminate the cancer. However, regulatory T cells (Tregs) and suppressor cells can inhibit this response, creating an immunosuppressive tumor microenvironment. Various strategies have been suggested to counteract these inhibitory pathways. CAF: Cancer-associated fibroblast; CAR: Chimeric antigen receptor; CSF-1R: Colony-stimulating factor 1 receptor; CTLA4: Cytotoxic T-lymphocyte associated protein 4; DLL: Delta-like ligand; MDSC: Myeloid-derived suppressor cell; MHC: Major histocompatibility complex; MQ: Macrophage; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; TCR: T cell receptor
Fig. 4
Fig. 4
An overview of chimeric antigen receptor (CAR) T cell therapy concept. CAR T cell therapy is a treatment approach, whereby T cells from an individual are modified in a laboratory setting to possess the ability to identify specific antigens found on cancer cells, leading to their elimination. (1) This process involves removing autologous T cells from the patient's blood. (2) Subsequently, the T cells are manipulated by introducing a gene encoding a specialized receptor, known as a CAR, into their genetic makeup through viral vectors. (3) This genetic alteration results in the expression of the CAR protein on the surface of the patient's T cells, thereby creating CAR T cells. These CAR T cells are then multiplied and expanded in laboratory conditions, producing millions of them. (4) Eventually, these CAR T cells are administered to the patient through intravenous infusion. (5) The CAR T cells attach themselves to the cancer cells by binding to the antigens present on their surface and proceed to eradicate the cancer cells. EGFR: Epidermal growth factor receptor; FAP: Fibroblast activation protein; MSLN: Mesothelin; PDAC: Pancreatic ductal adenocarcinoma; ScFv: Single-chain variable fragment; TAA: Tumor-associated antigen; TSA: Tumor-specific antigen
Fig. 5
Fig. 5
The emerging role of genome editing technology CRISPR/Cas9 in pancreatic cancer treatment. Utilizing CRISPR/Cas9 technology, autologous T cells are genetically modified to eliminate or alter genes that contribute to T cell exhaustion or resistance to immunotherapy. Once modified, these cells are reinfused into the patient, effectively improving the eradication of pancreatic ductal adenocarcinoma (PDAC) cells. TAA: Tumor-associated antigen; TCR: T cell receptor; TSA: Tumor-specific antigen
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