Nava Lauson, C. B. | Search bioRxiv

bioRxiv2023

LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness.

The lysine-specific histone demethylase 1A (LSD1) has been described to play a role in antitumor immunity; however, the role of LSD1 in shaping CD8+ T cell (CTL) differentiation and function is not understood. Here, we showed that pharmacological inhibition of LSD1 (LSD1i) in CTL elicited phenotypic and functional alterations of the CTL that led to robust antitumor immunity in the context of adoptive T cell therapy (ACT). In addition, the combination of anti-PDL1 therapy with LSD1i-based ACT resulted in a complete tumor eradication and long-lasting tumor-free survival. This study demonstrated that LSD1i together with anti-PDL1 therapy complement each others deficiencies and produce a better tumor response in a melanoma model, in which both immune and epigenetic therapy alone have shown limited efficacy. Collectively, these results set the translational potential of modulating LSD1 to improve antitumoral responses generated by ACT and anti-PDL1 therapy, which provide a strong rationale for a combination trial of LSD1i and immunotherapy.

immunology↗

bioRxiv2021

GZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in early-stage colorectal tumors and predict poor clinical outcome.

Tumor contexture has emerged as a major prognostic determinant and tumor infiltrating CD8+ T cells have been associated with a better prognosis in several solid tumors, including early-stage colorectal cancer (CRC). However, the tumor immune infiltrate is highly heterogeneous and understanding how the interplay between different immune cell compartments impacts on the clinical outcome is still in its infancy. Here, we describe in a prospective cohort a novel CD8+ T effector memory population, which is characterized by high levels of Granzyme K (GZMKhigh CD8+ TEM) and is correlated with CD15high tumor infiltrating neutrophils. We provide both in vitro and in vivo evidence of the role of stromal cell-derived factor 1 (CXCL12/SDF-1) in driving functional changes on neutrophils at the tumor site, promoting their retention and increasing the crosstalk with CD8+ T cells. Mechanistically, as a consequence of the interaction with neutrophils, CD8+ T cells are skewed towards a CD8+ TEM phenotype and produce high levels of GZMK, which in turn decreases E-cadherin pathway. The correlations of GZMKhigh CD8+ TEM and neutrophils with both tumor progression in mice and early relapse in CRC patients demonstrate the role of GZMKhigh CD8+ TEM in promoting malignancy. Indeed, a gene signature defining GZMKhigh CD8+ TEM was associated with worse prognosis on a larger independent cohort of CRC patients and a similar analysis was extended to lung cancer (TCGA). Overall, our results highlight the emergence of GZMKhigh CD8+ TEM in early-stage CRC tumors as a hallmark driven by the interaction with neutrophils, which could implement current patient stratification and be targeted by novel therapeutics.

immunology↗