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An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.

ABSTRACT: Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy^1-8. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like CD8 T cells give rise to more terminally differentiated, effector-molecule-expressing daughter cells. For many T cells to infiltrate the tumour, it is critical that this effector differentiation process occur. In addition, we show that these stem-like T cells reside in dense antigen-presenting-cell niches within the tumour, and that tumours that fail to form these structures are not extensively infiltrated by T cells. Patients with progressive disease lack these immune niches, suggesting that niche breakdown may be a key mechanism of immune escape.

SUBMITTER: Jansen CS

PROVIDER: S-EPMC7108171 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.

Jansen Caroline S CS Prokhnevska Nataliya N Master Viraj A VA Sanda Martin G MG Carlisle Jennifer W JW Bilen Mehmet Asim MA Cardenas Maria M Wilkinson Scott S Lake Ross R Sowalsky Adam G AG Valanparambil Rajesh M RM Hudson William H WH McGuire Donald D Melnick Kevin K Khan Amir I AI Kim Kyu K Chang Yun Min YM Kim Alice A Filson Christopher P CP Alemozaffar Mehrdad M Osunkoya Adeboye O AO Mullane Patrick P Ellis Carla C Akondy Rama R Im Se Jin SJ Kamphorst Alice O AO Reyes Adriana A Liu Yuan Y Kissick Haydn H

Nature 20191211 7787

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy<sup>1-8</sup>. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer. We find that CD8 T cells within tumours consist of distinct populations of terminally differentiated and stem-like cells. On proliferation, stem-like ...[more]

PMID: 31827286

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Project description:During embryogenesis, the neural stem cells (NSC) of the developing cerebral cortex are located in the ventricular zone (VZ) lining the cerebral ventricles. They exhibit apical and basal processes that contact the ventricular surface and the pial basement membrane, respectively. This unique architecture is important for VZ physical integrity and fate determination of NSC daughter cells. In addition, the shorter apical process is critical for interkinetic nuclear migration (INM), which enables VZ cell mitoses at the ventricular surface. Despite their importance, the mechanisms required for NSC adhesion to the ventricle are poorly understood. We have shown previously that one class of candidate adhesion molecules, laminins, are present in the ventricular region and that their integrin receptors are expressed by NSC. However, prior studies only demonstrate a role for their interaction in the attachment of the basal process to the overlying pial basement membrane. Here we use antibody-blocking and genetic experiments to reveal an additional and novel requirement for laminin/integrin interactions in apical process adhesion and NSC regulation. Transient abrogation of integrin binding and signalling using blocking antibodies to specifically target the ventricular region in utero results in abnormal INM and alterations in the orientation of NSC divisions. We found that these defects were also observed in laminin alpha2 deficient mice. More detailed analyses using a multidisciplinary approach to analyse stem cell behaviour by expression of fluorescent transgenes and multiphoton time-lapse imaging revealed that the transient embryonic disruption of laminin/integrin signalling at the VZ surface resulted in apical process detachment from the ventricular surface, dystrophic radial glia fibers, and substantial layering defects in the postnatal neocortex. Collectively, these data reveal novel roles for the laminin/integrin interaction in anchoring embryonic NSCs to the ventricular surface and maintaining the physical integrity of the neocortical niche, with even transient perturbations resulting in long-lasting cortical defects.

Dataset Information

An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.

Publications

An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.

Similar Datasets

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