A graphic that depicts the immune-suppressive TME

The pancreatic cancer tumor microenvironment (TME). The figure depicts the immune-suppressive TME, which consists of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Also shown is the extracellular matrix, vasculature, cancer-associated fibroblasts (CAFs), and major cytokines that have been implicated in TME regulation.

While immunotherapy has shown great promise in other solid tumors, such as lung cancer and melanoma, checkpoint inhibitors have not been successful thus far in pancreatic cancer.

Challenges of immunotherapy

This lack of success is believed to mainly be due to the general lack of neoantigens and the immune-suppressive tumor microenvironment (TME). The TME is composed of extracellular matrix (ECM), fibroblasts, and endothelial and hematopoietic cells, mainly of the myeloid lineage. Most immune-infiltrates are largely devoid of cytotoxic effector T-cells due to myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) contributing to local immunosuppression.

Future therapy

We envision a three-pronged approach, including chemotherapy or radiation to kill the tumor cell and release tumor antigens, depletion or reprogramming of myeloid suppressor cells to relieve local immune-suppression, and recruitment/augmentation of T-cell responses. We expect that a combination of immune-related agents will become an effective therapy in the future.

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