Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

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The blockade of immune checkpoints in cancer immunotherapy

The 2016 revision of the World Health Organization classification of lymphoid neoplasms

Characteristic patterns of gene expression measured by DNA microarrays have been used to classify tumors into clinically relevant subgroups. In this study, we have refined the previously defined subtypes of breast tumors that could be distinguished by their distinct patterns of gene expression. A total of 115 malignant breast tumors were analyzed by hierarchical clustering based on patterns of expression of 534 "intrinsic" genes and shown to subdivide into one basal-like, one ERBB2-overexpressing, two luminal-like, and one normal breast tissue-like subgroup. The genes used for classification were selected based on their similar expression levels between pairs of consecutive samples taken from the same tumor separated by 15 weeks of neoadjuvant treatment. Similar cluster analyses of two published, independent data sets representing different patient cohorts from different laboratories, uncovered some of the same breast cancer subtypes. In the one data set that included information on time to development of distant metastasis, subtypes were associated with significant differences in this clinical feature. By including a group of tumors from BRCA1 carriers in the analysis, we found that this genotype predisposes to the basal tumor subtype. Our results strongly support the idea that many of these breast tumor subtypes represent biologically distinct disease entities.

https://www.pnas.org/content/pnas/100/14/8418.full.pdf

Repeated observation of breast tumor subtypes in independent gene expression data sets

Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance, and immunopathology. Immune responses to foreign and self-antigens require specific and balanced responses to clear pathogens and tumors and yet maintain tolerance. Induction and maintenance of T cell tolerance requires PD-1, and its ligand PD-L1 on nonhematopoietic cells can limit effector T cell responses and protect tissues from immune-mediated tissue damage. The PD-1:PD-L pathway also has been usurped by microorganisms and tumors to attenuate antimicrobial or tumor immunity and facilitate chronic infection and tumor survival. The identification of B7-1 as an additional binding partner for PD-L1, together with the discovery of an inhibitory bidirectional interaction between PD-L1 and B7-1, reveals new ways the B7:CD28 family regulates T cell activation and tolerance. In this review, we discuss current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential.

PD-1 and its ligands in tolerance and immunity

Given the functional interdependencies between the molecular components in a human cell, a disease is rarely a consequence of an abnormality in a single gene, but reflects the perturbations of the complex intracellular and intercellular network that links tissue and organ systems. The emerging tools of network medicine offer a platform to explore systematically not only the molecular complexity of a particular disease, leading to the identification of disease modules and pathways, but also the molecular relationships among apparently distinct (patho)phenotypes. Advances in this direction are essential for identifying new disease genes, for uncovering the biological significance of disease-associated mutations identified by genome-wide association studies and full-genome sequencing, and for identifying drug targets and biomarkers for complex diseases.

Network Medicine: A Network-Based Approach to Human Disease

Molecular Signatures Implicate Innate Immune Cells, Fibrosis, and Angiogenesis in Survival Following R-CHOP Treatment of Diffuse Large B Cell Lymphoma

Background Clinical studies over the last 20 years using more intensive cytostatic regimens show improved results in children and adolescents with aggressive non-Hodgkin's lymphoma and in adult patients specifically with Burkitt's lymphoma. Material and methods We present a retrospective analysis of the use of the Berlin-Frankfurt-Munster (BFM) regimen for patients older than 15 years from three Norwegian university hospitals during the 1992-99 period. Results Survival data for 24 patients 15-69 years old with Burkitt's lymphoma/B-cell acute lymphoblastic leukaemia (B-ALL) show an estimated overall five year survival of 70% (75% for Burkitt's lymphoma only). Eight of ten adolescent patients 15-20 years old with other aggressive lymphomas were alive and disease free at last follow-up. All nine patients given the regimen after failure of prior therapy died of lymphoma within six years. Interpretation The BFM regimen yields impressive results as the primary treatment of adolescent and adult patients with Burkitt's lymphomas/B-ALL.

Intensiv kjemoterapi ved Burkitts lymfom og aggressivt non-Hodgkins lymfom

Summary: Register data suggest that patients with Hodgkin’s disease (HD) given high-dose therapy (HDT) with peripheral blood progenitor cells (PBPC) have a less favourable prognosis as compared to those given bone marrow as stem cell support. Since this can be due to infusion of tumour cells contaminating the PBPC grafts, we initiated a feasibility study in which PBPC grafts from HD patients were purged by CD34 + cell enrichment. Controversy exists about whether the use of CD34 +

Hodgkin's disease High-dose therapy in patients with Hodgkin's disease: the use of selected CD34 + cells is as safe as unmanipulated peripheral blood progenitor cells

Stein Kvaløy

Papers

Molecular Signatures Implicate Innate Immune Cells, Fibrosis, and Angiogenesis in Survival Following R-CHOP Treatment of Diffuse Large B Cell Lymphoma

Intensiv kjemoterapi ved Burkitts lymfom og aggressivt non-Hodgkins lymfom

Hodgkin's disease High-dose therapy in patients with Hodgkin's disease: the use of selected CD34 + cells is as safe as unmanipulated peripheral blood progenitor cells