Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy

SIMPLE SUMMARY: Reshaped pancreatic tumor microenvironment by chemotherapy, ultimately preventing or promoting tumor progression, is presented by the alteration of malignant, stromal cells, and immune cells, in a quantitative, functional, and spatial manner. They were studied predominantly in two cohorts, which include pancreatic cancer with borderline resectable and locally advanced disease (and minor resectable disease) under neoadjuvant chemotherapeutic regimens and most resectable and metastatic disease under adjuvant chemotherapeutic regimens. ABSTRACT: The dynamic tumor microenvironment, especially the immune microenvironment, during the natural progression and/or chemotherapy treatment is a critical frontier in understanding the effects of chemotherapy on pancreatic cancer. Non-stratified pancreatic cancer patients always receive chemotherapeutic strategies, including neoadjuvant chemotherapy and adjuvant chemotherapy, predominantly according to their physical conditions and different disease stages. An increasing number of studies demonstrate that the pancreatic cancer tumor microenvironment could be reshaped by chemotherapy, an outcome caused by immunogenic cell death, selection and/or education of preponderant tumor clones, adaptive gene mutations, and induction of cytokines/chemokines. These outcomes could in turn impact the efficacy of chemotherapy, making it range from synergetic to resistant and even tumor-promoting. Under chemotherapeutic impact, the metastatic micro-structures in the primary tumor may be built to leak tumor cells into the lymph or blood vasculature, and micro-metastatic/recurrent niches rich in immunosuppressive cells may be recruited by cytokines and chemokines, which provide housing conditions for these circling tumor cells. An in-depth understanding of how chemotherapy reshapes the tumor microenvironment may lead to new therapeutic strategies to block its adverse tumor-promoting effects and prolong survival. In this review, reshaped pancreatic cancer tumor microenvironments due to chemotherapy were reflected mainly in immune cells, pancreatic cancer cells, and cancer-associated fibroblast cells, quantitatively, functionally, and spatially. Additionally, small molecule kinases and immune checkpoints participating in this remodeling process caused by chemotherapy are suggested to be blocked reasonably to synergize with chemotherapy.