ORCID

0000-0002-9906-7058

Keywords

Immunometabolism, GPR84, nutrient sensing receptor, mitochondrial fitness, PD-1 resistance, cancer immunotherapy.

Subject Categories

Cancer Biology | Cell Biology

Abstract

The tumor microenvironment (TME) remains a major barrier to effective cancer immunotherapy. Upon entering tumors, T cells encounter a hostile environment characterized by nutrient deprivation, hypoxia, acidosis, and immunosuppressive signals that collectively impair their survival, metabolic fitness, and effector function. The ability of T cells to adapt to these conditions is therefore a critical determinant of successful anti-tumor immunity. However, the pathways that link environmental signals to T-cell metabolic adaptation remain incompletely understood. This work investigates the role of the medium-chain fatty acid (MCFA)-sensing receptor GPR84 in regulating T-cell responses during cancer. Our findings show that loss of GPR84 enhances tumor control and promotes the accumulation of functionally superior CD4⁺ and CD8⁺ T cells within tumors. In the absence of GPR84, T cells exhibit increased proliferation, persistence, and polyfunctional cytokine production, together with reduced expression of inhibitory receptors associated with T-cell dysfunction. Mechanistically, GPR84 deficiency improves metabolic fitness by enhancing mitochondrial activity and cellular bioenergetics, enabling T cells to better adapt to the metabolic challenges of the TME. In adoptive cell therapy models, GPR84-deficient T cells display superior expansion and antitumor activity, resulting in improved control of tumor growth. Importantly, pharmacological inhibition of GPR84 recapitulates many of these effects and enhances the efficacy of existing immunotherapeutic approaches. Collectively, these findings establish GPR84 as a critical regulator of T-cell metabolic adaptation and antitumor function and reveal extracellular lipid sensing as a targetable pathway in cancer immunity. Proposing GPR84 inhibition as a promising strategy to improve the effectiveness of T cell-based immunotherapies.

Completion Date

2026

Semester

Summer

Committee Chair

Nguyen, Hung

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

PDF

Document Type

Dissertation

Language

English

Release Date

8-15-2028

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Available for download on Tuesday, August 15, 2028

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