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Page 2 of 14         Diab et al. J Cancer Metastasis Treat 2022;8:42  https://dx.doi.org/10.20517/2394-4722.2022.60

               INTRODUCTION
               Pancreatic adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths and is expected to
                                        [1,2]
               be the second cause by 2030 . Multiple factors contribute to the dismal prognosis of PDAC, including
               resistance to chemotherapy and propensity for early metastasis . Mutations in four main genes support the
                                                                    [3]
               evolution of PDAC, which activate mutations in Kras and loss-of-function mutations in TP53,
                                             [3]
               P16/CDKN2A, and SMAD4/DPC4 . Current standard chemotherapeutic regimens, such as FOLFIRINOX
               and gemcitabine/nab-paclitaxel, only modestly improve survival . Additionally, immunotherapy, which has
                                                                     [4]
               revolutionized the treatment of patients with other malignancies, has been largely ineffective in pancreatic
               cancer . The exception is a small subset of patients with microsatellite instability-high disease, but those
                     [5]
               only account for approximately 1% of all patients .
                                                        [6]
               One of the key features of PDAC that support its chemoresistance is its desmoplastic stroma which prevents
                                                  [7]
               the delivery of chemotherapeutic agents . Moreover, its tumor microenvironment (TME) comprises a
               number of non-neoplastic cell populations, such as cancer-associated fibroblasts and suppressive immune
                                                           [3]
               cells, that prevent effector immune cell infiltration . Novel research over the last few years, coupled with
               advances in technology such as single-cell sequencing, has improved our understanding of TME and the
               many processes that occur both intra- and intertumorally, and has provided the space to test innovative
               treatment combinations that provide the basis for future efforts in diseases that have traditionally been very
               difficult to treat . This review highlights the different immune cell populations in the TME of PDAC.
                            [3]

               CANCER-ASSOCIATED FIBROBLASTS
               Cancer-associated fibroblasts (CAFs) are central to the development of the non-neoplastic components of
                       [8]
               the TME . Although not immune cells, CAFs influence the interplay between cancer cells and immune cells
               in the TME either through secreted factors or direct cell-cell interactions . Initially thought to exclusively
                                                                             [8]
               arise from PSCs, studies now suggest that CAFs can arise from different populations, including: PSCs ,
                                                                                                        [9]
               circulating bone marrow-derived cells called fibrocytes , adipose-derived mesenchymal stem cells
                                                                  [10]
               (MSCs) , and epithelial and endothelial cells through epithelial- and endothelial-to-mesenchymal
                      [11]
               transition [12,13] . The old concept that CAFs are solely tumor-promoting has been challenged by recent efforts
               to target the stromal aspect of PDAC . Evidence suggests that subpopulations of CAFs restrain tumor
                                                [14]
               growth rather than promote it , explaining why non-selective targeting of CAFs results in conflicting
                                          [14]
               outcomes . For example, depleting alpha-smooth muscle actin (α-SMA)-positive cells reduced desmoplasia
                       [14]
               in samples from PKT and KPC mice but resulted in highly undifferentiated tumors, further diminished
               intratumoral blood vessels with evident hypoxic necrosis, and shorter survival . Deletion of type I collagen
                                                                                 [14]
               in αSMA-positive myofibroblasts augmented immune suppression and resulted in a more aggressive cancer
               phenotype [15,16] . Similar findings were observed when treated with an inhibitor of Smoothened, which is
               overexpressed  on  CAFs,  or  neoplastic  cell  deletion  of  Sonic  Hedgehog  1,  a  major  mediator  of
               desmoplasia [17,18] . These findings explain the poor survival outcomes observed in a phase I/II trial of sonic
               hedgehog inhibitor, IPI-926, in combination with chemotherapy .
                                                                     [19]

               Single-cell RNA sequencing by Elyada, Hosein, and others shows heterogeneity in the CAF population that
               is present within the stroma of PDAC and confirms the presence of at least three different types of CAFs:
               myofibroblastic, inflammatory, and  antigen-presenting [Figure 1] [20-24] . These distinct CAF populations are
               stimulated through different pathways/cytokines, play different roles in PDAC, and reside in specific areas
               in the TME relative to cancer cells [20-24] .


               Myofibroblastic CAFs
               Myofibroblastic CAFs (myCAFs), reside in the periglandular region and have an alpha-smooth muscle actin
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