Potentiating immunotherapy in “immune-cold” solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering

TL;DR

A new genetic plasmid vector enhances T cell immunity in 'immune-cold' tumors, improving immunotherapy outcomes without major side effects.

Contribution

A tumor-targeted plasmid vector is developed to simultaneously modulate T cell immunity through LIGHT and αCD3 expression.

Findings

PαCD3&LIGHT promotes T cell infiltration and activation in solid tumors.

The plasmid enhances checkpoint inhibitor and CAR-T cell therapy efficacy in immune-cold tumors.

PαCD3&LIGHT suppresses tumor progression in melanoma, colon, and breast cancers.

Abstract

We engineer a tumor-targeted genetic plasmid vector (PαCD3&LIGHT) to systematically modulate T cell immunity. The tumor-specific telomerase reverse transcriptase (TERT) promoter drives simultaneous expression of tumor necrosis factor superfamily member 14 (LIGHT) and membrane-anchored anti-CD3 single-chain variable fragment (αCD3), which are important immunomodulators with closely clinical relevance. Secreted LIGHT induces high endothelial venule formation and chemokine secretion to recruit circulating lymphocytes, while remodeling extracellular matrix to facilitate immune cell penetration into tumor parenchyma. αCD3 establishes artificial immunological synapses between tumor cells and T lymphocytes. This dual mechanism synergistically establishes tertiary lymphoid structures de novo even within deep tumor regions, harboring stem cell-like CD8+ T cells and driving sustained immunity. Concurrently, αCD3-mediated T cell redirection not only amplifies TCR signaling but also reverses exhausted T cells. The orchestrated T cell immunity significantly potentiates checkpoint inhibitor and chimeric antigen receptor (CAR)-T cell therapies in “immune-cold” tumors without obvious side effects and also remarkably enhances the outcome of human CAR-T cells, demonstrating translational potential in solid tumor immunotherapy.

•PαCD3&LIGHT specifically drives the expression of αCD3 and LIGHT in tumors•PαCD3&LIGHT synergistically enhances T cell infiltration, activation, and proliferation•PαCD3&LIGHT inhibits progression of melanoma, colon carcinoma, and breast cancer•PαCD3&LIGHT augments ICIs and CAR-T cell efficacy without obvious systemic toxicity

PαCD3&LIGHT specifically drives the expression of αCD3 and LIGHT in tumors

PαCD3&LIGHT synergistically enhances T cell infiltration, activation, and proliferation

PαCD3&LIGHT inhibits progression of melanoma, colon carcinoma, and breast cancer

PαCD3&LIGHT augments ICIs and CAR-T cell efficacy without obvious systemic toxicity

He et al. develop a tumor-targeted genetic plasmid vector (PαCD3&LIGHT) that comprehensively modulates T cell anti-tumor immunity. PαCD3&LIGHT effectively suppresses the progression of multiple “immune-cold” solid tumors. Crucially, it also significantly potentiates the efficacy of ICIs and CAR-T cell therapies and reduces the systemic toxicity.

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