Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal cancer, accounting for 3.2% of new cancer cases yearly but nearly 8% of all yearly cancer mortalities. Over the past twenty years, our understanding of cancer biology has greatly improved which has resulted in vastly improved prognoses for many cancers. However, the prognosis of pancreatic ductal adenocarcinoma has not improved despite the advance in cancer treatments. This is especially apparent with cancer immunotherapies, a newer therapeutic strategy that utilizes the innate defense mechanism of the body to target malignancies. Immune checkpoint inhibitors are a type of cancer immunotherapy that act by inhibiting the PD-1/PD-L1 and CTLA-4 immune checkpoint pathways and allowing T lymphocytes to proliferate and generate an antitumor response. They have greatly improved the prognosis for many types of malignancies, but clinical studies show that immune checkpoint inhibition has had a limited effect on the prognosis of PDAC. Recent studies have demonstrated that the immune microenvironment of PDAC is highly immunosuppressive, which is a probable factor in limiting the therapeutic efficacy of immune checkpoint inhibitors. Myeloid derived suppressor cells (MDSCs) are a main component of the immune microenvironment in PDAC. They are immature cells of myeloid origin that express CD11b+Gr-1+ on their surface, making them phenotypically distinct from mature dendritic cells. Their infiltration of the PDAC microenvironment early on in the course of the disease is promoted in a large part by the cytokine GM-CSF. MDSCs are believed to contribute to the limited efficacy of immune checkpoint inhibitor therapy both directly and indirectly. Indirect mechanisms are mediated by promoting the activity of other immunosuppressive cells in the PDAC microenvironment such as tumor associated macrophages and regulatory T lymphocytes. MDSCs induce the transformation of naïve CD4+ T lymphocytes into protumorigenic regulatory T lymphocytes. They also promote the polarization of macrophages to the tumor associated macrophage phenotype (IL-10high IL-12low) by secreting IL-10, which decreases IL-12 synthesis by macrophages present in the tumor microenvironment. On top of mediating immunosuppression through other cell types, MDSCs directly mediate immunosuppression by decreasing the amounts of amino acids necessary for anti-tumor immunity in the tumor microenvironment and disrupting the activity of antigen presenting cells and the signaling needed to initiate a cytotoxic T lymphocyte response. The decreased amount of arginine limits the ability of T cells to proliferate, resulting in a weaker cytotoxic response. These mechanisms limit the antitumor response against pancreatic ductal adenocarcinoma, resulting in the decreased response to immune checkpoint inhibitor therapy observed in clinical trials. Future attempts to strengthen the anti-tumor immune response must be combinatorial therapies that incorporate therapeutic strategies that seek to alleviate MDSC-mediated immunosuppression of T lymphocytes from the tumor microenvironment in addition to the more widely available immune checkpoint inhibitor therapy. Such therapeutics are currently being studied in murine models and have shown promising preliminary results but have yet to have been examined in clinical trials. These therapies are an ideal avenue to explore in a search for more effective therapy for this highly lethal disease.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第17976号 / 医博第3840号 / 新制||医||1001(附属図書館) / 80820 / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸口田 淳也, 教授 宮地 良樹, 教授 長澤 丘司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18131号 / 医博第3851号 / 新制||医||1001(附属図書館) / 30989 / 京都大学大学院医学研究科医学専攻 / (主査)教授 千葉 勉, 教授 坂井 義治, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18133号 / 医博第3853号 / 新制||医||1001(附属図書館) / 30991 / 京都大学大学院医学研究科医学専攻 / (主査)教授 坂田 隆造, 教授 瀬原 淳子, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19560号 / 医博第4067号 / 新制||医||1013(附属図書館) / 32596 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 小川 修, 教授 長澤 丘司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21419号 / 医博第4409号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 小川 誠司, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21455号 / 医博第4422号 / 新制||医||1033(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 湊谷 謙司, 教授 浅野 雅秀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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