Combination, Modulation and Interplay of Modern Radiotherapy with the Tumor Microenvironment and Targeted Therapies in Pancreatic Cancer: Which Candidates to Boost Radiotherapy?

Abstract

Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly diverse disease with low tumor immunogenicity. PDAC is also one of the deadliest solid tumor and will remain a common cause of cancer death in the future. Treatment options are limited, and tumors frequently develop resistance to current treatment modalities. Since PDAC patients do not respond well to immune checkpoint inhibitors (ICIs), novel methods for overcoming resistance are being explored. Compared to other solid tumors, the PDAC's tumor microenvironment (TME) is unique and complex and prevents systemic agents from effectively penetrating and killing tumor cells. Radiotherapy (RT) has the potential to modulate the TME (e.g., by exposing tumor-specific antigens, recruiting, and infiltrating immune cells) and, therefore, enhance the effectiveness of targeted systemic therapies. Interestingly, combining ICI with RT and/or chemotherapy has yielded promising preclinical results which were not successful when translated into clinical trials. In this context, current standards of care need to be challenged and transformed with modern treatment techniques and novel therapeutic combinations. One way to reconcile these findings is to abandon the concept that the TME is a well-compartmented population with spatial, temporal, physical, and chemical elements acting independently. This review will focus on the most interesting advancements of RT and describe the main components of the TME and their known modulation after RT in PDAC. Furthermore, we will provide a summary of current clinical data for combinations of RT/targeted therapy (tRT) and give an overview of the most promising future directions.

Keywords: immune checkpoint inhibition; immunotherapy; pancreatic cancer; radiotherapy; targeted therapy; tumor microenvironment.

Figure 1

An overview of how radiotherapy affects the PDAC’s TME. Abbreviation: PDAC: pancreatic ductal adenocarcinomas; TME: tumor microenvironment; MDSCs: myeloid-derived suppressor cells; G-MDSCs: granulocytic myeloid-derived suppressor cells; MHC: major histocompatibility complex; TAMs: tumor-associated macrophages; TANs: tumor-associated neutrophils; CAF: cancer-associated fibroblasts; myCAFs: myofibroblastic cancer-associated fibroblasts; iCAFs: inflammatory cancer-associated fibroblasts; apCAFs: antigen-presenting cancer-associated fibroblasts; ROS: reactive oxygen species; DAMPs: damage-associated molecular patterns; TLS: tertiary lymphoid structures; TILs: tumor-infiltrating lymphocytes; Teff: effector T cells; Treg: regulatory T cells; MCSF: macrophage colony-stimulating factor.

Figure 2

Selected promising clinical perspectives of tRT in PDAC. Abbreviation: R0: R0 resection; APC: antigen-presenting cell; PFS: progression-free survival; SBRT: stereotactic body radiotherapy; TAMs: tumor-associated macrophages; MDSCs: myeloid-derived suppressor cells; VEGF: vascular endothelial growth factor; ↑: increased; ↓: decreased.