Biology subjects

Glatz, K.

Publications and source records attributed to Glatz, K..

3 recordsLinked to original sources

bioRxiv2025

Longitudinal profiling of tumor-reactive T cells during TIL therapy in metastatic melanoma

Adoptive cell therapy (ACT) with expanded autologous tumor-infiltrating lymphocytes (TILs) can induce durable responses in metastatic melanoma, yet many patients relapse. We profiled tumor-reactive T cell dynamics during TIL therapy using single-cell RNA and TCR sequencing from seven patients to elucidate underlying reasons. We found that tumor-reactive T cells preferentially expanded early during ex vivo TIL culture, transitioning from exhausted to reinvigorated effector states. Particularly, CD8+ exhausted T cells (Tex) and CD4+ follicular helper T cell (Tfh), but not CD4+ Tex, were efficiently reinvigorated. Further, we resolved the heterogeneity of tumor-reactive CD8+ and CD4+ subsets, defining unique signatures for their identification during TIL expansion. In addition, non-responders (NRs) exhibit increased levels of Type 17 T cells in TIL products, suggesting a potential association with resistance to therapy. After transfer, tumor-reactive clones rapidly extravasated and established a stem-like reservoir. However, in NRs, CD4+ regulatory T cells (Tregs) expanded de novo and tumor-reactive CD8+ T cells reacquired exhaustion markers, limiting their functionality. By contrast, responders (Rs) retained a pool of less differentiated, stem-like cells. Collectively, these data provide a comprehensive analysis of T cell fates during TIL-ACT providing the basis for new approaches to enhance therapeutic strategies.

immunology↗

bioRxiv2021

Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade

Immune checkpoint blockade (ICB) has significantly improved the prognosis of cancer patients, but the majority experience limited benefit, evidencing the need for new therapeutic approaches. Upregulation of sialic acid-containing glycans, termed hypersialylation, is a common feature of cancer-associated glycosylation, driving disease progression and immune escape via the engagement of Siglec-receptors on tumor-infiltrating immune cells. Here, we show that tumor sialylation correlates with distinct immune states and reduced survival in human cancers. The targeted removal of Siglec-ligands in the tumor microenvironment, using an antibody-sialidase conjugate, enhances anti-tumor immunity and halts tumor progression in several mouse tumor models. Using single-cell RNA sequencing, we reveal desialylation mechanistically to repolarize tumor-associated macrophages (TAMs) and identify Siglec-E on TAMs as the main receptor for hypersialylation. Finally, we show genetic and therapeutic desialylation, as well as loss of Siglec-E, to synergize with ICB. Thus, therapeutic desialylation represents a novel immunotherapeutic approach, shaping macrophage phenotypes and augmenting the adaptive anti-tumor immune response.

immunology↗

bioRxiv2018

B cells sustain inflammation and improve survival in human melanoma

Tumor associated inflammation is one of important predictors of response to immune checkpoint blockade. Understanding molecular processes that regulate tumor inflammation is key to improve the efficacy of checkpoint blockade. Established mechanisms that underlie therapy response and resistance have centered on anti-tumor T cell responses.\n\nWe show that tumor-associated B cells are vital to T cell functions. They promote recruitment of CD8+ T cells through plasmablast-like cells with expression of pro- and anti-inflammatory factors. Plasmablast-like cells are associated with improved survival of patients with metastatic melanoma and their response to checkpoint blockade. Plasmablast-like B cells express chemokines for T cell-attraction. Depletion of tumor-associated B cells by anti-CD20 immunotherapy of metastatic melanoma patients causes a remarkable decrease in tumor CD8+ T cells. These findings indicate that tumor-associated B cells orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and are key to therapeutic response and patients overall survival.

cancer biology↗