Overcoming dysfunctional innate sensing in myeloid cells circumvents cancer vaccine resistance

ABSTRACT: Chronic pathologic conditions like cancer exploit checkpoints to suppress T cell cytotoxicity and immune activity. Vaccines aiming to induce and amplify tumor-specific T cell responses have received promising anti-tumor effect in early clinical trials. However, the underlying mechanism driving resistance are poorly understand. Here, we sought to elucidate the myeloid cell populations which act as cellular checkpoints after perturbing the immune equilibrium in tumors using a T cell nanovaccine. We performed single cell RNA-sequencing of over 60,000 tumor infiltrating leukocytes isolated from a temporal profile of response and resistance following sub-optimal therapy. Though antigen specific T cells were highly boosted by the nanovaccine (70% of CD8+ cells), these cells became terminally exhausted over time with restricted T cell receptor diversity. Within the myeloid compartment, a MHChi-M2 macrophage population became dominant among late-stage resistance timepoint, which also exhibited progressively decreased STING activation (especially type I interferon expression). Terminally exhausted T cells and MHChi-M2 macrophages co-occurred in late-stage resistance and expressed ligand-receptor pairs that suggest their direct interaction to mediate T cell dysfunction, corroborated by immunohistochemistry. We combined the nanovaccine with another nanoparticle therapy targeting the STING pathway, which shifted the myeloid compartment towards a less suppressive state and increased progenitor and effector antigen-specific T cells while limiting terminal exhaustion. This study comprehensively profiled the highly dimensional, temporal dynamics of acquired vaccine resistance and associated immune dysfunction and identified cell populations which could serve as therapeutic targets to improve T cell immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE199635 | GEO | 2024/03/01

REPOSITORIES: GEO