*3.2. Acquired Resistance to Immunotherapy, An Additional Source of Modifications to Tumors Which Can Be Exploited by OVs*

Acquired resistance to immunotherapy can be viewed as an acute case of tumor immunoediting. In the context of immunotherapy, the release from the constraints imposed by the immune checkpoints, enforces high selective pressure applied on cancer cells by TME-localized immune cells. Thus, clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein 9 (Cas9)—mediated knockout screens identified genes related to IFN-γ, in addition to TNF-α and antigen presentation pathways as required for the T-cell mediated killing and its enhancement by anti-PD1 antibodies [132–134]. Similarly, truncation in the β2-microglobulin gene resulting in defects in MHC-I-mediated antigen presentation and loss-of-function mutations to JAK1 or JAK2, implying defects to the transduction of antiviral IFN signals; mediate resistance to PD-1 blockade in melanoma [135]. Given that immunostimulatory roles for PRRs have been identified in immunotherapy settings [136–140], they may also be targeted in acquired resistance to this form of therapy, with profound implications to the susceptibility of such edited tumors to OVs. Together, these studies show how escape from immune pressure, in the context of immunoediting in the course of tumor progression, or in the context of immunotherapy; can directly contribute to reduced resistance to infection of cancer cells with OVs.
