Favorable Alteration of Tumor Microenvironment by Immunomodulatory Cytokines for Efficient T-Cell Therapy in Solid Tumors

AbstractUnfavorable ratios between the number and activation status of effector and suppressorimmune cells infiltrating the tumor contribute to resistance of solid tumors to T-cell basedtherapies. Here, we studied the capacity of FDA and EMA approved recombinant cytokinesto manipulate this balance in favor of efficient anti-tumor responses in B16.OVA melanomabearing C57BL/6 mice. Intratumoral administration of IFN-?2, IFN-?, TNF-?, and IL-2 significantlyenhanced the anti-tumor effect of ovalbumin-specific CD8+ T-cell (OT-I) therapy,whereas GM-CSF increased tumor growth in association with an increase in immunosuppressivecell populations. None of the cytokines augmented tumor trafficking of OT-I cellssignificantly, but injections of IFN-?2, IFN-? and IL-2 increased intratumoral cytokine secretionand recruitment of endogenous immune cells capable of stimulating T-cells, such asnatural killer and maturated CD11c+ antigen-presenting cells. Moreover, IFN-?2 and IL-2increased the levels of activated tumor-infiltrating CD8+ T-cells concomitant with reductionin the CD8+ T-cell expression of anergy markers CTLA-4 and PD-1. In conclusion, intratumoraladministration of IFN-?2, IFN-? and IL-2 can lead to immune sensitization of theestablished tumor, whereas GM-CSF may contribute to tumor-associated immunosuppression.The results described here provide rationale for including local administration of immunostimulatorycytokines into T-cell therapy regimens. One appealing embodiment of thiswould be vectored delivery which could be advantageous over direct injection of recombinantmolecules with regard to efficacy, cost, persistence and convenienc