Immune microenvironment and immunotherapy prospects

Tumor-reprogrammed myeloid cells not only create a tolerogenic environment by blocking T cell functions and proliferation, but also promote tumor growth by promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition (EMT), and metastasis formation.The most investigated tumor related myeloid cells in PDAC are MDSCs and TAMs. MDSCs are a heterogeneous population of immature bone-marrow-derived cells able to suppress immune responses in TME. Pancreatic cancer cells can induce the mobilization of MDSCs from bone marrow and circulate systematically before being recruited into the TME.With the progressing of the primary tumor, on one hand, pancreatic tumor cells directly produce granulocyte macrophage colony stimulating factor (GM-CSF) to promote MDSCs accumulation in the TME, on the other hand, the hypoxic environment upregulates the secretion of hypoxia-inducible factor 1, which serves as a key mediator for MDSC recruitment.The MDSCs in TME suppress T lymphocytes through direct contact and/or through a combination of multiple major mediators such as inducible nitric oxide synthase, cyclooxygenase-2, prostaglandin E2, transforming growth factor (TGF-β), IL-10 and Tregs, et al.What worth mentioning is the interaction between MDSCs and T cells. Laura et al observed that MDSCs are harmless when contacting with resting T cells and become functionally active only in the presence of activated T cells, a crucial interaction capable of inducing a number of events including IL-10 release, STAT3 activation, programmed death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) up-regulation.

TAM differentiation relies on the NOTCH/recombination signal-binding protein for the Ig κ J region signaling pathway and are the major leukocyte population infiltrating cancers.They are attracted into the pancreas by chemoattractants present in the tumor stroma like IL-4 and colony stimulating factor-1 (CSF-1). They can also be generated by a polarization switch from inflammatory M1 macrophages to a tumor-promoting M2-like phenotype.M2 macrophages in tumors is related to early metastasis, tumor recurrence and ultimately reduced overall survival.Targeting chemokine receptor (CCR) 2 positive TAMs alone improves antitumor immunity in preclinical models, and enhanced antitumor immunity and chemotherapeutic responses are observed when in combination with targeting C-X-C chemokine receptor (CXCR) 2 positive tumor associated neutrophils.Genetic or pharmacologic inhibition of phosphoinositide 3-kinase (PI3K) γ, a key macrophage lipid kinase, restores antitumor immune responses and improves responsiveness to standard-of-care chemotherapy in PDAC.

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Immunotherapy: Open Access