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Zouine, A.

Publications and source records attributed to Zouine, A..

2 recordsLinked to original sources
bioRxiv2022

TREM1+ regulatory myeloid cells expand in steatohepatitis-HCC and associate with poor prognosis and therapeutic resistance to anti-PD-1 blockade

Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral and non-viral etiologies. Immune checkpoint blockade primarily benefits patients with viral HCC. Expansion of suppressive myeloid cells is a hallmark of chronic inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance in the steatohepatitis setting. Here, we present a high resolution atlas of hepatic innate immune cells from patients with HCC that unravels a steatohepatitis contexture characterized by the emergence of high entropy myeloid cell states and myeloid-biased NK cell differentiation. We identify a discrete population of tumor-infiltrating myeloid cells, predominant in the steatohepatitis setting, that expresses a variety of myeloid lineage-affiliated genes, including granulocyte, macrophage and dendritic cell features, and can be identified in HCC tumors based on selective dual expression of TREM1 and CD163. Functional characterization reveals that TREM1+ CD163+ myeloid cells highly express TGF{beta} and IL-13RA, localize to HCC fibrotic lesions, and potently suppress T cell effector functions ex vivo, a function further potentiated by TREM1 engagement. We refer to this population as TREM1+ CD163+ regulatory myeloid cells (TREM1+CD163+ Mreg). Deconvolution analyses in large cohorts of patients with HCC and other solid tumors reveals that the density of TREM1+ CD163+ Mreg increases in advanced stages, associates with poor prognosis, and therapeutic resistance to PD-1 blockade. Our data support myeloid subset-targeted immunotherapies to treat HCC and identify TREM1 as a therapeutic target. HIGHLIGHTSO_LIAtlas of hepatic innate immune cells (100,000 transcriptomes) from patients with HCC C_LIO_LICore signatures to identify, discriminate and localize innate lymphoid and myeloid cells C_LIO_LIA population of TREM1+CD163+ myeloid cells, referred to as TREM1+CD163+ Mreg, expands in steatohepatitis HCC C_LIO_LITREM1+CD163+ Mreg express granulocyte- and macrophage/dendritic cell-lineage genes C_LIO_LITREM1+CD163+ Mreg potently suppress T cell effector functions, which is potentiated by TREM1 engagement by cognate ligands C_LIO_LITREM1+CD163+ Mreg produce high levels of TGF{beta} and populate fibrotic lesions C_LIO_LIThe density of TREM1+CD163+ Mreg increases in advanced HCC and associate with poor patient survival C_LIO_LIThe density of TREM1+CD163+ Mreg associates with resistance to immune checkpoint blockade in other solid tumors C_LI

immunology↗
bioRxiv2022

Long-lived central memory γδ T cells confer protection against murine cytomegalovirus reinfection

The involvement of {gamma}{delta} TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. {gamma}{delta} T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of {beta} T cell deficient mice in order to analyze the memory potential of {gamma}{delta} T cells. As for CMV-specific {beta} T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ {gamma}{delta} TEM that principally localized in infected organ vasculature. Typifying T cell memory, {gamma}{delta} T cell expansion/proliferation in organs and blood was higher and more efficient after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection involved the T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR {delta} chain repertoire as evidenced by next generation sequencing. The {gamma}{delta} T cell secondary response to MCMV was composed by a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, Long-term-primed {gamma}{delta} TCM cells, but not {gamma}{delta} TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. Overall, our study uncovered memory properties of long-lived TCM {gamma}{delta} T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches. AUTHOR SUMMARYCytomegalovirus (CMV) is a widespread, latent virus that can cause severe organ disease in immune-compromised patients. Anti-CMV memory immune responses are essential to control viral reactivation and/or reinfection events that commonly take place in solid organ transplantation. The role of {gamma}{delta} T-cell receptor bearing lymphocytes could be crucial in this context where immunosuppressive/ablative treatments cause suboptimal and/or delayed {beta} T cell responses. Here we asked whether {gamma}{delta} T cells could compensate for the absence of {beta} T cells in the long-term control of mouse CMV infection. Three months post-primary viral challenge in {beta}-T cell deficient mice, {gamma}{delta} T cells displayed similar features as cytolytic, CMV-specific {beta} CD8 T cells. We showed that previous priming with CMV endowed {gamma}{delta} T cells with an enhanced antiviral potential and that long-term maintenance of {gamma}{delta}-mediated antiviral protection was dependent on {gamma}{delta} central memory T cells (TCM). The {gamma}{delta} T cell response to a secondary CMV challenge was dependent on {gamma}{delta} TCR-signaling and generated a private TCR {delta} repertoire as observed in human. Our results sustain the adaptive-like properties of these unconventional T cells and reveal the interest of targeting {gamma}{delta} TCM subset in novel antiviral vaccination approaches.

immunology↗