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Review
. 2020 Feb 15;19(1):32.
doi: 10.1186/s12943-020-01151-3.

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

Jia-Qiao Fan  1 , Meng-Fei Wang  2 , Hai-Long Chen  2 , Dong Shang  3 , Jugal K Das  4 , Jianxun Song  5
Affiliations
Review

Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma

Jia-Qiao Fan et al. Mol Cancer. .

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an incurable cancer resistant to traditional treatments, although a limited number of early-stage patients can undergo radical resection. Immunotherapies for the treatment of haematological malignancies as well as solid tumours have been substantially improved over the past decades, and impressive results have been obtained in recent preclinical and clinical trials. However, PDAC is likely the exception because of its unique tumour microenvironment (TME). In this review, we summarize the characteristics of the PDAC TME and focus on the network of various tumour-infiltrating immune cells, outlining the current advances in PDAC immunotherapy and addressing the effect of the PDAC TME on immunotherapy. This review further explores the combinations of different therapies used to enhance antitumour efficacy or reverse immunodeficiencies and describes optimizable immunotherapeutic strategies for PDAC. The concordant combination of various treatments, such as targeting cancer cells and the stroma, reversing suppressive immune reactions and enhancing antitumour reactivity, may be the most promising approach for the treatment of PDAC. Traditional treatments, especially chemotherapy, may also be optimized for individual patients to remodel the immunosuppressive microenvironment for enhanced therapy.

Keywords: Adoptive cell therapy; Immune checkpoint inhibitor; Immunotherapy; Myeloid-derived suppressor cells; Neoantigens; Pancreatic ductal adenocarcinoma; Regulatory T lymphocytes; Tumour microenvironment; Tumour-associated antigens; Tumour-associated macrophages; Tumour-infiltrating lymphocytes; Vaccines.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The graphic abstract of PDAC TME.• From the right upper side to the left low side, we summarize the progression of PDAC from PanIN and the distribution of different cells in TME. The yellow area represent the area mainly comprising different advanced stage of epithelial tissue from normal acinar to PanIN and invasive cancer nest, as well as monocyte-like cells; the reddish area present the area comprising mainly matrix including fibrotic matrix, pancreatic stellate cells, cancer associated fibroblasts, TLS, as well as accumulated effector lymphocytes. The cancer nests look like islands in the stroma desert; Treg cells surround the PanIN and establish a TSA specific suppressive condition to support PDAC progression; MDSCs appear at very early stage of the PDAC progression and disperse the whole lesion of tumor; TAMs locate majorly at the invasive front of the tumor and promote angiogenesis, lymphogenesis and metastasis; DCs are scarce and restricted in PanIN and TLS; CAFs and PSCs are the major source of tumor stromal matrix, they can also adhere infiltrating T lymphocytes, keep them outside of cancer nest and result effector T cell anergy; TLS localize in the tumor stroma and consist of proliferating effector cells as well as Treg cells, tumor specific anti-tumor and pro-tumor reactivity present concordantly
Fig. 2
Fig. 2
The molecular interaction of different cells in TME. The cancer cells of PDAC exploit several mechanisms including cell surface molecule and soluble factors to establish immunosuppressive TME through accumulating and activating immune suppressive cells, and inhibiting antitumor effector cells directly and indirectly; suppressive cells can inhibit the function of effector cells through nutrition depletion, phenotype alternation, apoptosis and anergy; Treg cells may play a central role in the establishment of immunosuppressive TME of PDAC since they are in favor of establishing tumor specific immunotolerance and have extensive interaction with other cells
Fig. 3
Fig. 3
The mechanisms of Treg inhibit Tconv through APC. Treg and Tconv contact directly with the same APC and establish tumor specific suppressive TME. a: Treg capture and degradate CD86 on DC with CTLA4, the process occurs in LN/TLS and PanIN, activating Treg migrate to established tumor and transform to resting Treg and execute suppression; b: Treg (also Tconv) contact with APC through various pairs of ligand-receptor including of TCR/MHC, CD28/CD86, CD28/CD80, CTLA4/CD86, CTLA4/CD80, mature DC dominantly express high level of CD86 and combine with CD28 and CTLA4, MDSC preferentially express CD80 and combine with CTLA4, immature/inducible DC express both CD86 and CD80. Notably, MDSC express low level of MHC and enhance suppressive function of Treg with weak TCR signal, whereas DC express high level of MHC and promote Treg activation and proliferation; c: APC could transform each other with the effect of Treg and Tconv concordantly; d: APC inhibit Tconv through several soluble factors and induce Tconv anergy through weak/downregulating TCR signal; e: APC inhibit CD4+ Tconv directly and CD8+ Tconv indirectly mainly by downregulating IL-2 and IFN-γ et al., Treg cells could inhibit Tconv by depriving IL-2. Biophysical stability of CTLA4/CD28-CD80/CD86 polymer: CTLA4-CD80 > CTLA4-CD86 > CD28-CD86 > CD28- CD80
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