**7. Implications of Interferon Competency in Cancer Cells with HLA Reversible Cancers**

Cancer cells with defects in interferon pathways or NF-κB signaling pathways may not be amenable to the correction of HLA function via the expression of interferons (Figure 2, categories G,H). This is crucially important for some oncolytic approaches that are designed to exploit cancer cells that have deregulated interferon pathways [68]. At face value, these oncolytic agents would perhaps not be the first choice for patients with interferon-reversible soft HLA defects because, by definition, these tumors are likely to be interferon responsive and therefore the activity of these viruses would be limited.

However, the reality is more nuanced, because defects in interferon signaling can be at different stages of the pathway, with some cancer cells not able to express interferons and others not able to respond to them. In a stromal-rich tumor, fibroblasts and macrophages are likely to have the full capacity to detect oncolytic viruses and express interferons even if the cancer cells are defective [69]. Cells that can be stimulated by external interferon (with intact JAK/STAT signaling) would often have functional interferon regulatory factors (IRFs), and therefore be able to trigger ISRE to upregulate classical class I HLA expression. Conversely, cells with deficient JAK/STAT pathways could likely still upregulate HLA, but only if their own virus-sensing pathways remain intact. Consequently, a major subset of cancer cells with functional JAK/STAT pathways but defects in virus sensing and interferon expression, could likely upregulate HLA in response to interferons generated within the TME by an oncolytic virus interacting with stromal cells. However, this may be to the detriment of further oncolytic virus spread and lysis. Accordingly, matching the patient population to the oncolytic strategy is very important.

Some DNA viruses have sophisticated mechanisms to overcome interferon responses, for example the E1A protein and the VA RNAs in adenovirus, B8R and B18R/B19R in vac-

cinia, and ICP34.5, US11 and others in HSV-1 [70]. Adenoviruses, for example, can continue replicating despite triggering interferon and STING pathways, allowing both immune stimulation and lysis to happen concurrently [71]. When DNA viruses are genetically attenuated to render them interferon sensitive, the innate immune response works to limit viral replication [72]. Consequently, patients that are considered to have interferon-inducible HLA may be preferentially matched with viruses that can operate in a wider variety of interferon competent environments. This may be particularly true in heterogeneous tumors where there is likely to be a variety of different interferon defects in different populations of cancer cells, and also in those cancers with a high stromal cell content. In contrast, for viruses that are unavoidably dependent on dysfunctional interferon, it may be possible to achieve upregulation of HLA via interferon-independent pharmacological means such as HDAC inhibition [73].
