FIG. 1.

Preexisting autoimmune mechanisms modulating tumor growth in the context of autoimmunity. The pathogenesis of cancer in ADs can be divided into three distinct stages (A–C, top) over time of disease (bottom arrow). In the first stage or onset (A), autoimmunity develops in healthy individuals triggered by unknown environmental, genetic, or random factors. This stage can last for 3 to 4 years before clinical diagnosis. In the second stage (B), the AD is diagnosed, and chronic inflammatory mechanisms are established. Based on the balance between activating factors (ie, type I and II IFNs) and inhibitory factors (ie, expression of the coinhibitory molecules such as PD-L1 or CTLA-4) organ or tissue damage ensues. At this stage, responsive feedback loops are established to withstand changes in the AICOM resulting from activation of T cells, B cells, dendritic cells, and macrophages. In the third stage, tumors develop and start gradually modifying the ongoing AICOM through production of tumor-promoting factors to evade immune surveillance. However, immune cells already battling to control ADs showed signs of exhaustion or tolerogenic functional states evidence by the expression of coinhibitory molecules (arrows crossing from stage B, C). Under conditions different from cancer patients without autoimmunity, immunotherapy is required to contain tumor progression. ADs, autoimmune diseases; AICOM, autoimmune cytokine milieu; CTLA-4, cytotoxic T lymphocyte–associated protein 4; IFNs, interferons; MDSCs, myeloid-derived suppressor cells; MHC, major histocompatibility complex; PD-L1, programmed cell death-1 ligands; TAM, tumor-associated macrophages.