Inactivated Wild-Type Rotavirus

In the study, researchers found that rotavirus vaccines have immunostimulatory and oncolytic properties. In vitro, they can directly kill cancer cells with immunogenic cell death characteristics. In vivo, intratumoral rotavirus therapy has immune-dependent antitumor effects. In several immunocompetent mouse tumor models, intratumoral rotavirus overcame resistance to and synergized with immune checkpoint-targeted therapies. Inactivated rotavirus lost oncolytic activity but maintained synergy with immune checkpoint-targeted antibodies by upregulating the double-stranded RNA receptor retinoic acid-induced gene 1 (RIG-I). Rotavirus vaccines are clinical-grade products for use in pediatric and adult populations. Therefore, in situ immunization strategies using intratumoral attenuated rotavirus can be rapidly implemented in the clinic.

Here, the researchers found that the IT rotavirus + IP anti-CTLA-4 combination therapy had the same synergistic effect in both immunized and non-immunized mice (Figure 1A). In contrast to active rotavirus, Intratumoral (IT) inactivated rotavirus had no antitumor efficacy when used as a monotherapy (Figure 1B). However, unexpectedly, IT inactivated rotavirus synergized and overcame resistance to anti-CTLA-4 as effectively as IT active rotavirus (Figure 1B). Because inactivated rotavirus behaved the same as active rotavirus when used in combination with anti–CTLA-4, researchers focused on the genes that were commonly regulated by the cancer cells by both states of rotavirus. They identified the list of genes represented in the heatmap in Figure 1C. The study found that the inactivated rotavirus was still able to induce a strong expression of the type I IFN pathway: interferon regulatory factor 4 (IRF4) and IRF7 were still among the top up-regulated genes with log2 fold changes above 2 with inactivated rotavirus. Next, they compared the list of genes differentially expressed in EMT6 cancer cells after rotavirus exposure with the list of genes co-regulated by active and inactivated rotavirus in A20 cancer cells. The study found that only six genes were commonly upregulated in EMT6 cells with active rotavirus, A20 cells with inactivated rotavirus, and A20 cells with inactivated rotavirus (Figure 1D).

Figure 1. Intrinsic rotavirus components are driving the proinflammatory features necessary for the synergy with anti–CTLA-4. (Shekarian T, et al., 2019)