Biology subjects

Kirchhammer, N.

Publications and source records attributed to Kirchhammer, N..

4 recordsLinked to original sources

bioRxiv2025

Integrated single cell analysis identifies CD39+ tumor-associated NK cells with cytotoxic potential in lung cancer

Natural killer (NK) cell-targeting immunotherapies are emerging, yet the differentiation and functional states of tumor-infiltrating NK cells remain poorly understood. Using matched single-nucleus RNA and ATAC sequencing of non-small cell lung cancer (NSCLC) specimens, we resolved the transcriptional and epigenetic landscape of intratumoral NK cells. We identified two tumor-associated NK (taNK) cell subsets marked by ITGAE (CD103) and ITGA1 (CD49a) that display features of tissue residency and dysfunction while preserving cytotoxic function. Trajectory and regulon analyses revealed an inflammation-driven transition from early GZMK NKs toward an ENTPD1+ (CD39) effector state characterized by interferon-stimulated gene (ISG) programs. Functional profiling established CD39 taNK as the dominant cytotoxic NK cell population with superior killing capacity that is further potentiated by NKG2A blockade. This study offers mechanistic insights into NK cell differentiation in NSCLC and establishes CD39 taNK cells as a targetable effector population for immunotherapy. One sentence summaryMultiomic analysis identifies CD39+ tumor-associated NK cells as a cytotoxic effector state in NSCLC responsive to NKG2A blockade.

immunology↗

bioRxiv2021

Successful IL-12 cancer immunotherapy requires NK cell-derived CCL5 for anti-tumor DC-T cell crosstalk

T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the IFN{gamma}-IL-12 pathway relies on the ability of a population of tissue-resident NK (trNK) cells to orchestrate an anti-tumor microenvironment. Particularly, utilizing an engineered adenoviral platform, we show that paracrine IL-12 enhances functional DC-CD8 T cell interactions to generate adaptive anti-tumor immunity. This effect depends on the abundance of trNK cells and specifically their capacity to produce the cDC1-chemoattractant CCL5. Failure to respond to IL-12 and other IFN{gamma}-inducing therapies such as immune checkpoint blockade in tumors with low trNK cell infiltration could be overcome by intra-tumoral delivery of CCL5. Our findings reveal a novel barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC crosstalk can be enhanced to promote anti-tumor immunity and overcome resistance. SignificanceWe identified the lack of CCL5-producing, tissue-resident NK (trNK) cells as a barrier to T cell-focused therapies. While IL-12 induces anti-tumoral DC-T cell crosstalk in trNK cellrich tumors, resistance to IL-12 or anti-PD-1 in trNK cellpoor tumors can be overcome by the additional delivery of CCL5.

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↗

bioRxiv2019

Hyperglycemia enhances cancer immune evasion by inducing alternative macrophage polarization through increased O-GlcNAcylation

Diabetes mellitus (DM) significantly increases the risk for cancer and cancer progression. Hyperglycemia is the defining characteristic of DM and tightly correlates with a poor prognosis in cancer patients. The hexosamine biosynthetic pathway (HBP) is emerging as a pivotal cascade linking high glucose, tumor progression and impaired immune function. Here we show that enhanced glucose flow through the HBP drives cancer progression and immune evasion by increasing O-GlcNAcylation in tumor-associated macrophages (TAMs). Increased O-GlcNAc skewed macrophage polarization to a M2-like phenotype. HBP or O-GlcNAcylation inhibition reprogrammed TAMs to an anti-tumoral phenotype. Finally, we found an upregulation of M2 markers on TAMs in DM2 patients with colorectal cancer compared to non-diabetic normoglycemic patients. Our results provide evidence for a new and targetable mechanism of cancer immune evasion in patients with hyperglycemia, advocating for strict control of hyperglycemia in cancer patients.\n\nSignificanceHyperglycemia increases O-GlcNAc levels in TAMs, programing them to a pro-tumorigenic phenotype (M2-like), contributing to cancer progression. Inhibition of O-GlcNAcylation could therefore be used to reprogram intratumoral macrophages to an anti-tumoral phenotype.

cancer biology↗