Promoting the Recruitment, Engagement, and Reinvigoration of Effector T Cells via an Injectable Hydrogel with a Supramolecular Binding Capability for Cancer Immunotherapy

Abstract

T cells play a basic and key role in immunotherapy against solid tumors, and efficiently recruiting them into neoplastic foci and sustaining long-term effector function are consistent goals that remain a critical challenge. Here, an injectable alginate-based hydrogel with abundant β-cyclodextrin (ALG-βCD) sites is developed and intratumorally injected to recruit CCR9⁺ CD8⁺ T cells (a subset of T cells with robust antitumor activity) via the trapped chemokine CCL25. In the meantime, an intravenously injected adamantane-decorated anti-PD1 antibody (Ad-aPD1) would hitchhike on recruited CCR9⁺ CD8⁺ T cells to achieve the improved intratumoral accumulation of Ad-aPD1. Moreover, the Ad-PD1 and Ad-PDL1 antibodies are immobilized in the ALG-βCD hydrogel through supramolecular host-guest interactions of Ad and βCD, which facilitate engagement between CD8⁺ T cells and tumor cells and reinvigorate CD8⁺ T cells to avoid exhaustion. Based on this treatment strategy, T cell-mediated anticancer activity is promoted at multiple levels, eventually achieving superior antitumor efficacy in both orthotopic and postsurgical B16-F10 tumor models.

Keywords: T cell hitchhiking; cancer immunotherapy; engagement between T cells and tumor cells; recruiting CCR9+CD8+ T cells; reinvigoration of CD8+ T cells; supramolecular binding.