Clinical impact of chemotherapy to improve tumor microenvironment of pancreatic cancer

Abstract

A perioperative multimodal strategy including combination chemotherapy and radiotherapy, in addition to surgical resection, has been acknowledged to improve patient prognosis. However chemotherapy has not been actively applied as an immunomodulating modality because of concerns about various immunosuppressive effects. It has recently been shown that certain chemotherapeutic agents could modify tumor microenvironment and host immune responses through several underlying mechanisms such as immunogenic cell death, local T-cell infiltration and also the eradication of immune-suppressing regulatory cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells. With the better understanding of the cell components in the tumor microenvironment and the effect of chemotherapy to improve tumor microenvironment, it has been gradually clear that the chemotherapeutic agents is two-edged sword to have both immune promoting and suppressing effects. The cellular components of the tumor microenvironment include infiltrating T lymphocytes, dendritic cells, regulatory T cells, tumor associated macrophages, myeloid derived suppressor cells and cancer associated fibroblasts. Based on the better understanding of tumor microenvironment following chemotherapy, the treatment protocol could be modified as personalized medicine and the prognosis of pancreas cancer would be more improved utilizing multimodal chemotherapy. Here we review the recent advances of chemotherapy to improve tumor microenvironment of pancreatic cancer, introducing the unique feature of tumor microenvironment of pancreatic cancer, interaction between anti-cancer reagents and these constituting cells and future prospects.

Circulating regulatory T cell subsets predict overall survival of patients with unresectable pancreatic cancer

“…The change of T cell proportion may be altered by the chemotherapy or by the shrinkage of the tumor. Many studies reported that chemotherapy agents could change tumor microenvironment through various mechanisms, such as increasing lymphocyte infiltration, depletion of Tregs and inducing differentiation of MDSC (32). However, for the circulating lymphocytes, it was still unclear.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…136,147,150,151 Additional details about ICD-associated signaling pathways and resistance mechanisms can be found in various publications from us and others. [2][3][4]7,40,[152][153][154][155] Of note, only a limited number of cell death inducers can elicit bona fide ICD, and this capacity cannot be predicted on the basis of structural or functional similarities. Thus, while cisplatin and oxaliplatin both induce RCD at least in part by forming interand intra-strand DNA adducts, 156 only the latter induces ICD.…”

CAR T‐cell therapy for pancreatic cancer

“…Common PDAC chemotherapeutic agents include 5‐FU, gemcitabine (GEM), and combination therapies such as FOLFIRINOX (5‐FU, leukcovorin, irinotecan, oxaliplatin) . These chemotherapeutic agents, as well as commonly used radiation regimens, can modify the tumor microenvironment and host immune responses via several underlying mechanisms, such as immunogenic cell death, local T‐cell infiltration, and eradication of immunosuppressing Tregs, and myeloid derived suppressor cells (MDSCs); this provides a rationale for their use neoadjuvantly in CAR T‐cell therapy . The number of CD4 + and CD8 + cells increased significantly after neoadjuvant chemoradiation using gemcitabine and TS‐1 in mice and higher CD4 count was shown to be a good prognostic marker .…”