Interferons and the Immunogenic Effects of Cancer Therapy

Abstract

Much of our understanding on resistance mechanisms to conventional cancer therapies such as chemotherapy and radiation has focused on cell intrinsic properties that antagonize the detrimental effects of DNA and other cellular damage. However, it is becoming clear that the immune system and/or innate immune signaling pathways can integrate with these intrinsic mechanisms to profoundly influence treatment efficacy. In this context, recent evidence indicates that interferon (IFN) signaling has an important role in this integration by influencing immune and intrinsic/non-immune determinants of therapy response. However, IFN signaling can be both immunostimulatory and immunosuppressive, and the factors determining these outcomes in different disease settings are unclear. Here I discuss the regulation and molecular events in cancer that are associated with these dichotomous functions.

Figure 1. Cancer cell intrinsic and immune determinants of response to chemotherapy and radiation can be regulated by the opposing functions of interferon signaling

DNA damage caused by chemotherapy or radiation initiates either apoptosis or regulated necrosis to release DAMPs. These DAMPs can be well-known immune activators such as HMGB1, ATP, or calreticulin (CRT) that get either secreted extracellularly or exposed on the plasma membrane. These DAMPs activate antigen presenting cells (APCs), with HMGB1 binding to TLR4 shown as an example. Intracellular DAMPs can be nucleic acids that include mitochondrial DNA (mtDNA), single-stranded DNA (ssDNA), ssRNA, or double-stranded RNA (dsRNA). The DNA is sensed by the cytosolic DNA sensor cGAS to activate STING, while the RNA is detected by TLRs and RLRs. Additionally, DNA from the tumor can be transferred to antigen presenting cells (APCs) where it can activate STING as well. STING and TLRs/RLRs increase type one interferon (IFN-I) production. Like HMGB1/TLR4, this enhances APC cross-priming of T cells. Tumor-reactive T cells produce high levels of interferon gamma (IFNg) and lyse cancer cells. Both IFN-I and IFNg have additional anti-tumor effects such as promoting cancer cell death. However, both IFN-I and IFNg can also promote immunosuppression and cancer cell intrinsic resistance to therapy. IFN-I can enhance IL-10 production and upregulate PD-L1 on APCs, making them immune suppressive. IFN-I and IFNg can upregulate PD-L1 on cancer cells in a phenomenon called adaptive resistance that leads to T cell exhaustion. In cancer cells, unphosphorylated STAT1 (U-STAT1) accumulates and sustains the expression of a subset of ISGs that include the Interferon-Related DNA Damage Resistance Signature (IRDS). The IRDS mediates resistance to radiation and chemotherapy, possibly by increasing DNA repair or inhibiting NK and T cell function through unclear ISGs and mechanisms. However, one mechanism involves the activation of RLRs by stromal cell-derived exosomes (tan box). This also increases IRDS and enhances the transcription of NOTCH3 target genes, which expands therapy-resistant tumor-initiating cells (not shown). Blue boxes indicate anti-tumor and immunostimulatory effects. Cyan boxes indicate pro-tumor and immuosuppressive effects.