Adoptive cellular therapy prevents reconstitution of myeloid-derived suppressor cells in the glioma tumor microenvironment

TL;DR

Adoptive cellular therapy prevents myeloid-derived suppressor cells from accumulating in brain tumors, improving immune response and survival in glioma models.

Contribution

This study reveals a novel mechanism by which adoptive cellular therapy limits MDSC accumulation in the tumor microenvironment through TAM-derived CCL12 reduction.

Findings

Adoptive cellular therapy prevents MDSC accumulation in the tumor microenvironment while allowing their reconstitution in secondary lymphoid organs.

Adoptive cellular therapy reduces CCL12 levels in the tumor microenvironment, and TAM-derived CCL12 neutralization inhibits MDSC migration in vitro.

Loss of intratumoral immunosuppressive elements and TAM-derived CCL12 is associated with improved immune response after immunotherapy.

Abstract

Glioblastoma (GBM) is an aggressive brain cancer infiltrated by immunosuppressive myeloid-derived suppressor cells (MDSCs) and confers poor prognosis. To address this, our group developed an adoptive cellular therapy platform specifically for primary central nervous system (CNS) malignancies that yielded significant survival benefits against multiple brain cancer models. Preclinically, this platform establishes proof-of-concept for lymphodepletion achieved through host conditioning with total body irradiation (TBI). While host conditioning is thought to remove immunosuppressive elements, the aim of this study was to determine how immune recovery is affected by adoptive cellular therapy.

The adoptive cellular therapy platform includes myeloablative TBI, hematopoietic stem cell rescue, tumor-specific T cells, and dendritic cell vaccines. KR158B glioma-bearing mice were treated with adoptive cellular therapy and secondary lymphoid organs were evaluated using flow cytometry, spatial genomics, and multiplex protein analysis. Single-cell transcriptomics and trans-well migration assay evaluated the role of CCL12 on MDSC migration.

We show that adoptive cellular therapy allows for reconstitution of MDSC and tumor-associated macrophages in secondary lymphoid organs but prevents their accumulation in the tumor microenvironment (TME). This allows for the increased engraftment and activation of T cells within the TME. Next, we show that adoptive cellular therapy decreases CCL12 in the TME and neutralization of TAM-derived CCL12 in vitro inhibits MDSC migration in glioma.

These findings suggest a previously unrecognized association between both loss of intratumoral immunosuppressive elements after immunotherapy and TAM-derived CCL12, a chemokine that promotes MDSC migration. Future in vivo studies will evaluate the causal role of CCL12 on MDSC recruitment in glioma.

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