Enhanced antitumor effects by combining IL-12 gene electrotransfer with anti-PD1 in preclinical metastatic cancer model

Abstract

Abstract The survival and expansion of effector cytotoxic T lymphocytes (CTLs) during an immunological response are critical for the successful elimination of cancer cells. Among the factors that regulate the immune response, interleukin-12 (IL-12), is known to stimulate growth and survival of T cells. Major differences exist between these lymphokines in their capacity to act on various T-cell types such as CD4+ or CD8+ and effector versus memory T lymphocytes. PD1 expression can have a negative effect on effector or memory T-cell populations causing anergy or cell death. Limited information is available regarding the function of combining IL-12 gene electrotransfer (GET) with anti-PD1 in preclinical metastatic cancer models. Here, we report that IL-12 (GET) induced expansion of effector CD8 CTLs. Combining IL-12 GET with anti-PD1 i.p. injection resulted in long-term survival of CD8+PD1− T cells. Most significantly, the effector cytolytic activity of CTLs were expanded and maintained for up to 60 days, indicating that these cells do not differentiate into a memory functional phenotype. In a two site metastatic model, B16F10 melanoma cells expressing luciferase were injected via intraperitoneal route and B16.F10 cells (no luciferase) were injected subcutaneously. Results on day 60 using an In Vivo Imaging System (IVIS) illuminated a lower flux signal in intraperitoneal metastases. Simultaneously, the primary subcutaneous tumors completely regressed in 80% of these mice. The expression of CD44+ CD62L− increased with time, which was detected on CD8 CTLs, suggesting that the memory response was still active at 120 days. The present findings have practical implications for the combination of IL-12 gene electrotransfer with anti-PD1.