Challenges and Opportunities in Targeting the Complex Pancreatic Tumor Microenvironment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a 5-year survival rate of 13%. Surgical resection remains the only curative option as systemic therapies offer limited benefit. Poor response to chemotherapy and immunotherapy is due, in part, to the dense stroma and heterogeneous tumor microenvironment (TME). Opportunities to target the PDAC stroma may increase the effectiveness of existing or novel therapies. Current strategies targeting the stromal compartment within the PDAC TME primarily focus on degrading extracellular matrix or inhibiting stromal cell activity, angiogenesis, or hypoxic responses. In addition, extensive work has attempted to use immune targeting strategies to improve clinical outcomes. Preclinically, these strategies show promise, especially with the ability to alter the tumor ecosystem; however, when translated to the clinic, most of these trials have failed to improve overall patient outcomes. In this review, we catalog the heterogenous elements of the TME and discuss the potential of combination therapies that target the heterogeneity observed in the TME between patients and how molecular stratification could improve responses to targeted and combination therapies.

FIG 1.

Targeting the nonimmune stromal compartment of the PDAC TME. A summary of the current stromal-targeting therapies in PDAC, including (a) degradation of HA in ECM with hyaluronidase; (b) inhibiting hypoxia response in tumor cells with HIF-1α inhibitor and taking advantage of hypoxia with the use of hypoxia-activated prodrugs; (c) inhibiting angiogenesis with tyrosine kinase inhibitors; (d) targeting matrix-producing stromal cells by inhibiting the activity of PSCs with CXCR4 inhibitor, inhibiting PSC-derived Shh with antagonist, and inhibiting myCAFs with FAK inhibitors and iCAFs with IL-1, IL-6, and JAK antagonist. Alternatively, matrix-producing stromal cells are targeted to convert from CAFs to quiescent PSCs with ATRA and from myCAFs to tumor-restraining CAFs with synthetic retinoids. ATRA, all-trans retinoic acid; CAF, cancer-associated fibroblast; CXCR4, C-X-C chemokine receptor type 4; ECM, extracellular matrix; FAK, focal adhesion kinase; HA, hyaluronic acid; HIF-1α, hypoxia-inducible factor-1 alpha; iCAF, inflammatory cancer-associated fibroblast; IL-1, interleukin-1; IL-6, interleukin-6; JAK, Janus kinase; myCAF, myofibroblastic cancer-associated fibroblast; PDAC, pancreatic adenocarcinoma; PSC, pancreatic stellate cell; Shh, sonic hedgehog; TME, tumor microenvironment.

FIG 2.

Targeting the immune compartment of the PDAC TME. A summary of the current immune-targeting therapies in PDAC including (a) activating antitumor immune responses in CTLs with CD137 agonist, activating APC activity with CD40 agonist, FLT3 ligand, activating APCs and B cells with TLR9 agonist, and stimulating tumor cells with STING agonist to release more IFNs that activate CTLs; (b) inhibiting immune suppressive T_reg cells and TAMs with CCR2/CCR5 antagonist and inhibiting TAMs with CSF1R kinase inhibitor; (c) preventing CTL exhaustion with immune checkpoint blockades of CTLA-4, PD-1/PD-L1, TIGIT. APC, antigen-presenting cell; CCR2, C-C motif chemokine receptor 2; CCR5, C-C chemokine receptor 5; CSF1R, colony-stimulating factor-1 receptor; CTL, cytotoxic T-lymphocyte; CTLA-4, cytotoxic T-lymphocyte–associated protein 4; FLT3, FMS-related receptor tyrosine kinase 3; IFN, interferon; PDAC, pancreatic adenocarcinoma; STING, stimulator of interferon genes; TAM, tumor-associated macrophage; TIGIT, T-cell immunoreceptor with immunoglobulin and ITIM domains; TLR9, toll-like receptor 9; TME, tumor microenvironment; T_reg cell, regulatory T cell.