Fig. 5

Proposed model for the postulated functions of STAT1 in HR-DLBCL-NOS. Chronic exposure to IFNs and chemotherapeutic agents such as alkylating agents, topoisomerase inhibitors, HDAC inhibitors, or proteasome inhibitors, can lead to constitutive oncogenic upregulation of STAT1 and interferon signaling genes (ISGs) during tumor development [515–518, 524, 640–643] and select tumor clones resistant to a cytotoxic microenvironment and concurrently to genotoxic therapy [518]. The overall population of tumor cells is sensitive to cytotoxic factors of microenvironment and committed to death because of the secretion of cytotoxic ligands by host cells (T lymphocytes, B lymphocytes, tumor-associated macrophages, dendritic cells etc.) [518]. The majority of tumor cells are relatively sensitive to radio- and/or chemotherapy. However, a small fraction of tumor cells (HR-DLBCL cells) constitutively express STAT1/ISGs and are resistant to the cytotoxic microenvironment and genotoxic therapy. Oncogenic constitutive expression of STAT1 can activate the prosurvival secretome, including the interleukines IL6 and IL10 [322, 468, 644] and in turn, can enhance selective advantages of surrounding tumor cells [518]. Moreover, STAT1 pathway can be also activated in the context of IL6 and IL10 [322, 645], thereby generating auto-stimulatory feedback loops (IL6-IL16R-STAT1 and IL10-IL10R-STAT1). Thus, IFN/JAK pathway and chemotherapeutic agents may act in concert with other HR-DLBCL specific intrinsic signaling pathways such as IL10/IL10R-JAK1-TYK2 and or IL6/IL6R-gp130-JAK1/2-TYK2 to induce chemotherapy resistance. In addition, oncogenic JAK/STAT1α-autocrine signaling in HR-DLBCL causes enhanced expression of STAT1α dependent proto-oncogenes (i.e., DTX3L ARTD9, IRF2, MCL1, BCL2, BCL6), thereby stimulating proliferation and survival pathways [470]. In addition, oncogenic STAT1α signaling helps the tumors to escape the attack by the immune system (immunoediting) [473, 497, 526]. Conversely, STAT1β repress the transcriptional activation of anti-proliferative and pro-apoptotic genes (including tumor the suppressors IRF1 and TP53) [470, 471] as well as genes involved in immune surveillance [473, 497, 526]. Adapted from REF: [470, 471, 518]. Abbreviations: HR-DLBCL host response DLBCL, ARTD ADP-ribosyltransferase Diphteria toxin-like, STAT signal transducer and activator of transcription, ISG interferon stimulated gene, IL interleukin, JAK Janus kinase, TYK2 tyrosine kinase 2, IRF interferon response factor, BCL6 B cell lymphoma protein 6, BCL2 B cell lymphoma protein 2