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Today, improvements in diagnostic and therapeutic options allow patients with autoimmune diseases (ADs) to live longer and have more active lives compared with patients receiving conventional anti-inflammatory therapy just two decades ago. Current therapies for ADs aim to inhibit immune cell activation and effector immune pathways, including those activated by cytokines and cytokine receptors. Understandably, such goals become more complicated in patients with long-term established ADs who develop parallel chronic or comorbid conditions, including life-threatening diseases, such as cancer. Compared with the general population, patients with ADs have an increased risk of developing hematological, lymphoproliferative disorders, and solid tumors. However, the aim of current cancer therapies is to activate the immune system to create autoimmune-like conditions and eliminate tumors. As such, their comorbid presentation creates a paradox on how malignancies must be addressed therapeutically in the context of autoimmunity. Because the physiopathology of malignancies is less understood in the context of autoimmunity than it is in the general population, we undertook this review to highlight the peculiarities and mechanisms governing immune cells in established ADs. Moreover, we examined the role of the autoimmune cytokine milieu in the development of immune-related adverse events during the implementation of conventional or immune-based therapy.

Intratumoral phenotypic heterogeneity has been described in many tumor types, where it can contribute to drug resistance and disease recurrence. We analyzed ductal and neuroendocrine markers in pancreatic ductal adenocarcinoma, revealing heterogeneous expression of the neuroendocrine marker Synaptophysin within ductal lesions. Higher percentages of Cytokeratin-Synaptophysin dual positive tumor cells correlate with shortened disease-free survival. We observe similar lineage marker heterogeneity in mouse models of pancreatic ductal adenocarcinoma, where lineage tracing indicates that Cytokeratin-Synaptophysin dual positive cells arise from the exocrine compartment. Mechanistically, MYC binding is enriched at neuroendocrine genes in mouse tumor cells and loss of MYC reduces ductal-neuroendocrine lineage heterogeneity, while deregulated MYC expression in KRAS mutant mice increases this phenotype. Neuroendocrine marker expression is associated with chemoresistance and reducing MYC levels decreases gemcitabine-induced neuroendocrine marker expression and increases chemosensitivity. Altogether, we demonstrate that MYC facilitates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma, contributing to poor survival and chemoresistance.