Immunotherapy Synergizes with Chemotherapy Targeting Pancreatic Cancer

Abstract

Pancreatic adenocarcinoma is a devastating disease and has an extremely poor prognosis. Despite aggressive treatment approaches, including surgery, chemotherapy and radiation, the overall 5‐year survival rate is less than 5%. Therefore, the development of therapeutic strategies for advanced pancreatic cancer has traditionally been considered particularly challenging to improve clinical outcomes. Although immunotherapy that is designed to target tumor-associated antigens (TAAs) is a promising treatment approach, immunotherapy alone is limited by the number of cytotoxic T lymphocytes (CTLs) able to penetrate the large established pancreatic tumor. Even if large numbers of antigen-specific polyclonal CTLs were generated in vitro and injected into the patients, CTLs cannot penetrate into tumor sites because of stroma cells such as cancer-associated fibroblasts, tolerogenic dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), immunosuppressive tumor-associated macrophages and Tregs. Moreover, these cells produce immunosuppressive cytokines such as IL-10 and TGF-β; thus, clinical responses by immunotherapy alone cannot induce efficient antitumor immunity in patients with advanced pancreatic cancer. On the other hand, cytotoxic chemotherapy is well known to blunt immune responses, because of its toxicity for dividing cells including peripheral lymphoid tissue as well as the bone marrow. However, increasing evidence has been mounting to suggest that immunotherapy has the possibility of achieving better success when used in combination with chemotherapy [1]. For example, necrotic or apoptotic tumor cells induced by chemotherapy can be phagocytosed by DCs that are potent antigen-presenting cells, processed and presented to immune lymphocytes, followed by induction of antitumor immune responses. Different chemotherapeutic agents may kill tumor cells through an apparently homogeneous apoptotic pathway. Of note, treatment of pancreatic cancer cells with a standard cytotoxic agent for pancreatic cancer, gemcitabine, results in enhanced cross-presentation of TAAs by DCs and CTL induction [2]. Moreover, gemcitabine can also inhibit Tregs, B cells and MDSCs [2,3], but induce the proliferation of DCs [4]. These phenomena suggest that gemcitabine induces efficient CTL responses, improves the penetration of CTLs into the tumor parenchyma, and enhances tumor cell sensitivity to lyze antigen-specific CTLs. Thus, immunotherapy may mediate a potent antitumor effect when c ombined with chemotherapy.