The Tumor Microenvironment of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis along with rising incidence rates and will be responsible for many cancer deaths in the future [...].

immune privilege [26]. It is therefore important for TME factors to also be considered in the view of overcoming therapy resistance [12]. Some encouraging evidence comes, however, from studies on long-term survivors of PDAC. These recent studies have shown that the neoantigen quality (rather than quantity) can modulate immunogenicity in PDAC and have reported that both a high neoantigen number and an abundant CD8+ T-cell infiltrate was present in the tumors of long-term survivors, implying that the neoantigenic repertoire has been evolutionary selected in this cohort [27]. This underlines the importance of understanding and expanding our knowledge of the spectrum of tumor-immune interactions. This is especially important regarding immunotherapy. Early clinical trials with checkpoint inhibitors, including monotherapy with monoclonal antibodies that block PD-L1 from binding its ligand, have yielded rather disappointing results in pancreatic cancer, apart from a few cases with microsatellite instability [28,29]. Thus, studies to detect further potential predictive biomarkers correlated to immunotherapy outcomes are necessary. Based on immunopathology and gene expression approaches, the TME of most cancers can be broadly characterized as either T cell inflamed ("hot") or non-T cell inflamed ("cold"), depending on the frequency, composition and spatial organization of tumor-infiltrating lymphocytes (TILs) and immunomodulatory molecules [30,31] ( Figure 1A,B). Generally, T cell inflamed tumors exhibit improved responses to immunotherapies [31]. Moreover, histopathologic examination of the TME can also reveal critical tumor-intrinsic characteristics. For example, biologically aggressive PDACs display increased numbers of dissociative growing tumor cells exhibiting partial epithelial-mesenchymal transition (EMT)-features, termed tumor buds. Tumor budding is an independent adverse prognostic factor in PDAC and is associated with an immunosuppressive TME [32,33].
Cancers 2020, 12, x 2 of 4 cells, a phenomenon known as immune privilege [26]. It is therefore important for TME factors to also be considered in the view of overcoming therapy resistance [12]. Some encouraging evidence comes, however, from studies on long-term survivors of PDAC. These recent studies have shown that the neoantigen quality (rather than quantity) can modulate immunogenicity in PDAC and have reported that both a high neoantigen number and an abundant CD8+ T-cell infiltrate was present in the tumors of long-term survivors, implying that the neoantigenic repertoire has been evolutionary selected in this cohort [27]. This underlines the importance of understanding and expanding our knowledge of the spectrum of tumor-immune interactions. This is especially important regarding immunotherapy. Early clinical trials with checkpoint inhibitors, including monotherapy with monoclonal antibodies that block PD-L1 from binding its ligand, have yielded rather disappointing results in pancreatic cancer, apart from a few cases with microsatellite instability [28,29]. Thus, studies to detect further potential predictive biomarkers correlated to immunotherapy outcomes are necessary. Based on immunopathology and gene expression approaches, the TME of most cancers can be broadly characterized as either T cell inflamed ("hot") or non-T cell inflamed ("cold"), depending on the frequency, composition and spatial organization of tumor-infiltrating lymphocytes (TILs) and immunomodulatory molecules [30,31] (Figure 1A,B). Generally, T cell inflamed tumors exhibit improved responses to immunotherapies [31]. Moreover, histopathologic examination of the TME can also reveal critical tumor-intrinsic characteristics. For example, biologically aggressive PDACs display increased numbers of dissociative growing tumor cells exhibiting partial epithelial-mesenchymal transition (EMT)-features, termed tumor buds. Tumor budding is an independent adverse prognostic factor in PDAC and is associated with an immunosuppressive TME [32,33]. Thus, insights into the different landscapes of PDAC would promote our understanding of the biology behind the tumor-immune interactions and would support a more accurate prognostic and predictive stratification of patients for more efficient clinical management. Moreover, integrative approaches, which take into account intrinsic tumor features, such as morphology and genetic changes in the tumor cells as well as extrinsic features such as the immune landscape of the TME, would provide a more efficient tool to tackle this recalcitrant disease, towards a more individualized clinical management of PDAC patients. As newer treatment regimens become available, both in the adjuvant and in the neoadjuvant settings, including immunotherapy [30,34], these approaches would help selecting patient subsets for appropriate treatment modalities.
Funding: This research received no external funding.

Conflicts of Interest:
The author declares no conflict of interest. Thus, insights into the different landscapes of PDAC would promote our understanding of the biology behind the tumor-immune interactions and would support a more accurate prognostic and predictive stratification of patients for more efficient clinical management. Moreover, integrative approaches, which take into account intrinsic tumor features, such as morphology and genetic changes in the tumor cells as well as extrinsic features such as the immune landscape of the TME, would provide a more efficient tool to tackle this recalcitrant disease, towards a more individualized clinical management of PDAC patients. As newer treatment regimens become available, both in the adjuvant and in the neoadjuvant settings, including immunotherapy [30,34], these approaches would help selecting patient subsets for appropriate treatment modalities.
Funding: This research received no external funding.

Conflicts of Interest:
The author declares no conflict of interest.