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Single-cell sequencing reveals dynamic immune features of paraneoplastic pemphigus in a patient with follicular lymphoma

ABSTRACT: Background: Paraneoplastic pemphigus (PNP) is a highly fatal autoimmune blistering disease that commonly occurs in patients with underlying benign or malignant neoplasms. It poses significant challenges for diagnosis and treatment. To date, the cellular and molecular mechanisms underlying the pathogenesis of PNP remain largely unclear. Objective: This study aims to elucidate the cellular and molecular mechanisms of PNP, particularly when it occurs secondary to lymphoma, by analyzing the dynamic immune landscape throughout the course of treatment. Method: We performed single-cell transcriptome sequencing and single-cell T cell receptor (TCR) analysis on peripheral blood mononuclear cells (PBMCs) and bone marrow cells (BMCs) obtained from a patient with follicular lymphoma (FL) accompanied by PNP. Samples were collected at three critical time points: before treatment, during treatment, and after successful treatment. Result: Before treatment, we observed a specific enrichment of ITGAL+ T cells, abnormal γδT cell subtypes, and BCL2+ B cells in PBMCs. Notably, naïve T cells and an abnormal B cell subtype were also enriched in BMCs. The single-cell transcriptome results mapped the lymphoma-associated tumor microenvironment and revealed post-treatment immune reconstitution. This reconstitution involved activated DNA damage and T cell immune responses, which was further supported by the observation of a gradually expanded TCR clone as the treatment progressed. Conclusion: Our study delineates the dynamic immune landscape in a patient with FL-associated PNP throughout treatment, demonstrating that successful treatment correlates with immune reconstitution involving specific T cell responses and TCR clone expansion. These findings provide novel insights into the cellular and molecular mechanisms of PNP, especially in cases secondary to lymphoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318717 | GEO | 2026/03/18

REPOSITORIES: GEO

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Project description:Exhaustion markers are expressed by T lymphocytes in Follicular Lymphoma (FL). Through these, TIM-3 has been recently identified as a poor pronostic factor when expressed by FL CD4+ T cells. Before this study, there was no molecular characterization of unstimulated CD8+ T cells, expressing - or not - TIM-3. We used microarrays to compare the global gene expression profile between CD8+TIM-3+ T cells and CD8+TIM-3- T cells freshly sorted from follicular lymphoma biopsies. Abstract from the associated publication: Up-regulation of T-cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression by ex vivo cytotoxic T cells (CTL) from follicular lymphoma (FL) biopsies and their functional unresponsiveness that could limit the favorable impact of CTL on disease progression. We report a high percentage of CD8+TIM-3+ T cells in lymph nodes of FL patients. When compared to their CD8+TIM-3- counterparts, CD8+TIM-3+ T cells exhibited defective cytokine production following TCR engagement. Furthermore CD8+TIM-3+ T cells display ex vivo markers of lytic granule release and remain unresponsive to further TCR-induced activation of the lytic machinery. Although confocal microscopy showed that TIM-3 expression on CD8+ T cells correlated with minor alterations of immunological synapse, a selective reduction of ERK signaling in CD8+TIM-3+ T cells was observed by phospho-flow analysis. Finally, short relapse free survival despite rituximab(R)-chemotherapy was observed in patients with high content of TIM-3+ cells and a poor infiltrate of granzyme B+ T cells in FL lymph nodes. Together, our data indicate that, besides selective TCR early signaling defects, TIM-3 expression correlates with unresponsiveness of ex vivo CD8+ T cells in FL. They show that scores based on the combination of exhaustion and cytolytic markers in FL microenvironment might be instrumental to identify patients at early risk of relapses following R-chemotherapy.

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Single-cell sequencing reveals dynamic immune features of paraneoplastic pemphigus in a patient with follicular lymphoma

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