Emerging trends in the immunotherapy of pancreatic cancer

Abstract

Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the U.S., claiming approximately 43,000 lives every year. Much like other solid tumors, PC evades the host immune surveillance by manipulating immune cells to establish an immunosuppressive tumor microenvironment (TME). Therefore, targeting and reinstating the patient's immune system could serve as a powerful therapeutic tool. Indeed, immunotherapy has emerged in recent years as a potential adjunct treatment for solid tumors including PC. Immunotherapy modulates the host's immune response to tumor-associated antigens (TAAs), eradicates cancer cells by reducing host tolerance to TAAs and provides both short- and long-term protection against the disease. Passive immunotherapies like monoclonal antibodies or engineered T-cell based therapies directly target tumor cells by recognizing TAAs. Active immunotherapies, like cancer vaccines, on the other hand elicit a long-lasting immune response via activation of the patient's immune cells against cancer cells. Several immunotherapy strategies have been tested for anti-tumor responses alone and in combination with standard care in multiple preclinical and clinical studies. In this review, we discuss various immunotherapy strategies used currently and their efficacy in abrogating self-antigen tolerance and immunosuppression, as well as their ability to eradicate PC.

Keywords: Immunotherapy; PD-L1; Pancreatic cancer; Tumor associated antigen.

Figure 1. Pancreatic cancer cells establish an immunosuppressive TME

Cancer cells secrete various anti-inflammatory cytokines like IL-10, TGF-β, IL-23, along with angiogenic chemokines (e.g., CXCL1-3, CXCL5, CXCL12, CCL2, and VEGF-A), which generate an immunosuppressive TME and facilitate cancer initiation, progression and metastasis. Upregulation of the expression of these cytokines shifts the balance in TME, which facilitates the evasion from immune surveillance during PC progression [6, 8, 19, 24]. The PC immunosuppressive microenvironment also includes crosstalk between cancer cells and various myeloid and lymphoid subsets. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) express immuno-inhibitory ligands and reactive oxygen species that inhibit infiltration and activation of T and NK cells [3, 9, 10, 12]. MDSCs and cancer cells also secrete VEGFs that promote angiogenesis, which aids in the metastasis of the cancer cells [13]. PC tumor cells and pancreatic stellate cells (desmoplasia) secrete inhibitory cytokines and chemokines, and express inhibitory surface ligands such as programmed death ligand-1 (PD-L1) and galectin-1 (Gal-1) that lead to inactivation and apoptosis of cytotoxic (CD8⁺) and helper (CD4⁺) T-cells by programmed death receptor-1(PD-1) or Gal-1 binding receptor respectively [15, 16, 20, 21]. T_reg cells suppress the functions of activated T-cells and NK cells in the TME [12, 95]. In addition, the rigid architecture of pancreatic tumor bed provides physical barrier to T-cells infiltration thereby excluding them to the edge/boundary of the tumor and thus rendering the pancreatic tumor as an immunologically ‘cold’ tumor [–27]. All these cells are involved in maintenance of the immunosuppressive TME, and cancer progression.

Figure 2. CAR T-cells are genetically engineered T-cells expressing tumor antigen-specific chimeric TCR [119, 120]

The modified receptor is a chimera of a signaling domain of the TCR complex and an antigen-recognizing domain, such as a single chain fragment (scFv) of an antibody [121, 122]. CAR T-cells are not dependent on antigen presentation by MHC molecules expressed on APCs for antigen specific activation. Adoptive cell transfer of CAR T-cells involves the isolation, stimulation, expansion, transduction, and ultimately re-infusion of human T lymphocytes [123, 124]. First-generation TCRs included only the intracellular domain of the CD3ζ chain but did not show any significant in vivo efficacy in transgenic mouse model studies [125]. Second-generation CARs introduced additional co-stimulatory domains such as CD28, which significantly augmented CAR signaling, and improved cytokine production and T-cell proliferation, as well as differentiation, and survival [126, 127]. Third-generation CARs contain multiple co-stimulatory domains such as 4-1BB (CD137), and whether they have clinical benefit over second-generation CAR T-cells is still under investigation [122, 128, 129].