T-cell invigoration to tumour burden ratio associated with anti-PD-1 response

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Abstract

The clinical benefit of anti-PD-1 antibody treatment is dependent on the extent to which exhausted CD8 T cells are reinvigorated in relation to the tumour burden of the patient.

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Final version of 2009 AJCC melanoma staging and classification.

Charles M. Balch, Jeffrey Gershenwald, Seng-jaw Soong … (2010)

To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level. Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.

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Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.

Kristen E. Pauken, Morgan A. Sammons, Pamela M. Odorizzi … (2016)

Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.

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Extracting a Cellular Hierarchy from High-dimensional Cytometry Data with SPADE

Peng-Fei Qiu, Erin Simonds, Sean Bendall … (2011)

Multiparametric single-cell analysis is critical for understanding cellular heterogeneity. Despite recent technological advances in single-cell measurements, methods for analyzing high-dimensional single-cell data are often subjective, labor intensive and require prior knowledge of the biological system under investigation. To objectively uncover cellular heterogeneity from single-cell measurements, we present a novel computational approach, Spanning-tree Progression Analysis of Density-normalized Events (SPADE). We applied SPADE to cytometry data of mouse and human bone marrow. In both cases, SPADE organized cells in a hierarchy of related phenotypes that partially recapitulated well-described patterns of hematopoiesis. In addition, SPADE produced a map of intracellular signal activation across the landscape of human hematopoietic development. SPADE revealed a functionally distinct cell population, natural killer (NK) cells, without using any NK-specific parameters. SPADE is a versatile method that facilitates the analysis of cellular heterogeneity, the identification of cell types, and comparison of functional markers in response to perturbations.

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Author and article information

Journal

Title: Nature

Abbreviated Title: Nature

Publisher: Springer Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Created: April 10 2017

Publication date (Print): April 10 2017

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Article

DOI: 10.1038/nature22079

PMC ID: 5554367

PubMed ID: 28397821

SO-VID: b2c7a7c5-0c22-44c5-a893-93c5932d7591

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T-cell invigoration to tumour burden ratio associated with anti-PD-1 response

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Anti-Trafficking Review

Most cited references 6

Final version of 2009 AJCC melanoma staging and classification.

Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.

Extracting a Cellular Hierarchy from High-dimensional Cytometry Data with SPADE

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