Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy

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.

Single-cell RNA sequencing reveals the immune microenvironment landscape of osteosarcoma before and after chemotherapy

“…Similar to our findings, the study conducted by Víctor Sánchez-Margalet et al also reported that neoadjuvant chemotherapy leads to a reduction of NK cells, CD4 T cells (including Tregs cells) in peripheral blood of breast cancer (BRCA) patients, while CD8 T cells were decreased only in a minority of patients, which was consistent with our results [ 24 ]. Other studies also indicate that chemotherapy exerts a similar remodeling effect on T cell populations, thereby enhancing the ability to eliminate tumors [ [25] , [26] , [27] ]. Additionally, gene ontology (GO) analysis revealed that DEGs of T cell clusters were primarily enriched in multiple aspects, such as cell activation, adaptive immune response, and immune response to tumor cells ( Fig.…”

Pancreatic cancer environment: from patient-derived models to single-cell omics

“…In PC, there are a large number of stromal responses, which promote immune escape, tumor growth, and decrease parenchymal cells. 22 The targeted therapy drugs and newly discovered chemotherapeutic agents necessitate a representative study cohort and an appropriate pharmacogenomic platform. The preclinical PC PDX models are widely recognized as the gold standard as they are highly reliable and have significant predictive capabilities.…”