Intratumoral injection of IFN-β induces chemokine production in melanoma and augments the therapeutic efficacy of anti-PD-L1 mAb

Abstract

Despite recent advances in treatment for melanoma patients through using immune checkpoint inhibitors, these monotherapies have limitations and additional treatments have been explored. Type I IFNs have been used to treat melanoma and possess immunomodulatory effects including enhancement of T-cell infiltration. T-cell plays a critical role in immune checkpoint therapies via restoration of effector functions and tumor infiltration by T-cells predicts longer survival in a variety of cancer types. Moreover, tumor-infiltrating T-cells are associated with the expression of chemokines such as CCL5 and CXCR3 ligands in tumor tissues. We therefore investigated whether intratumoral injection of IFN-β induces the expression of CCL5 and CXCR3 ligands in melanoma cells and has additional antitumor effects when combined with anti-PD-L1 mAb treatment. IFN-β treatment enhanced CD8 T-cell infiltration into tumors and CCL5 and CXCR3 ligand expression. In vivo studies using a mouse model showed that monotherapy with IFN-β, but not with anti-PD-L1 mAb, inhibited tumor growth in comparison to control. However, the therapeutic efficacy of IFN-β was significantly enhanced by the addition of anti-PD-L1 mAb. This antitumor response of combination therapy was abrogated by anti-CD8 mAb and IFN-β augmented the neoantigen-specific T-cell response of anti-PD-L1 mAb. Our findings suggest that IFN-β induces the expression of CCL5 and CXCR3 ligands in melanoma, which could play a role in T-cell recruitment, and enhances the efficacy of anti-PD-L1 mAb treatment in a CD8-dependent manner.

Effect of CCL5 expression in the recruitment of immune cells in triple negative breast cancer

“…On the other hand, in melanoma, intratumoral injection of IFN-β induces expression of CCL5 and CXCR3 ligands and administration of IFN-β with anti-PD-1 monoclonal antibodies suppressed the tumor growth and prolonged the survival in a murine model 36 .…”

Sustained Inflammatory Signalling through Stat1/Stat2/IRF9 Is Associated with Amoeboid Phenotype of Melanoma Cells

“…Moreover, IFN-β increases tumour infiltration by immune cell subsets, including CD4+ and CD8+ T-cells [26]. Consistently, IFN-β treatment was shown to prolong survival and increase T-cell recruitment into the tumour tissue of B16F10-bearing mice, which could contribute to the therapeutic efficacy of immune checkpoint inhibitors [27]. Peritumourally administered IFN-β enhances the antitumor effect of anti-PD-1 antibody against B16F10 melanoma [28].…”

<p>Research Progress and Existing Problems for Abscopal Effect</p>

“…76 On the other hand, radiation therapy renders tumour cells more susceptible to immunity. Reits et al found that under high doses of radiation (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), the expression of the major histocompatibility complex I (MHC-I) increased in a dose-dependent manner. Increased MHC-I expression promoted the production of APCs and activated the effector T cells.…”

“… 15 Interferon-beta (IFN-β) also plays an important role in the activation of T cells. 16 Radiation therapy-induced IFN-β was also related to the development of the abscopal effect in patients with non-small cell lung cancer (NSCLC). 17 Shortly after the completion of radiation therapy (day 22), serum IFN-β levels in 7 respondents significantly increase from baseline.…”