SLAMF6 expression associates with survival in triple negative breast cancer.

We mined published microarray data (1) to understand the most significant gene expression differences in the tumors of triple negative breast cancer patients based on survival following treatment: dead or alive. We observed significant transcriptome-wide differential expression of SLAM family member 6, encoded by SLAMF6 when comparing the primary tumors of triple negative breast cancer patients dead or alive. Importantly, SLAMF6 expression was correlated with overall survival in basal subtype breast cancer, a molecular subtype sharing significant overlap with triple negative breast cancer. SLAMF6 may be of relevance as a biomarker or as a molecule of interest in understanding the etiology or progression of triple negative breast cancer.

System-wide hematopoietic and immune signaling aberrations in COVID-19 revealed by deep proteome and phosphoproteome analysis

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has become a global crisis. To gain systems-level insights into its pathogenesis, we compared the blood proteome and phosphoproteome of ICU patients with or without SARS-CoV-2 infection, and healthy control subjects by quantitative mass spectrometry. We find that COVID-19 is marked with hyperactive T cell and B cell signaling, compromised innate immune response, and dysregulated inflammation, coagulation, metabolism, RNA splicing, transcription and translation pathways. SARS-CoV-2 infection causes global reprogramming of the kinome and kinase-substrate network, resulting in defective antiviral defense via the CK2-OPN-IL-12/IFN-I axis, lymphocyte cell death via aberrant JAK/STAT signaling, and inactivation of innate immune cells via inhibitory SIRPA, SIGLEC and SLAM family receptor signaling. Our work identifies CK2, SYK, JAK3, TYK2 and IL-12 as potential targets for immunomodulatory treatment of severe COVID-19 and provides a valuable approach and resource for deciphering the mechanism of pathogen-host interactions.

Advances in Understanding the Roles of CD244 (SLAMF4) in Immune Regulation and Associated Diseases

Proteins in the signaling lymphocytic activating molecule (SLAM) family play crucial roles in regulating the immune system. CD244 (SLAMF4) is a protein in this family, and is also a member of the CD2 subset of the immunoglobulin (Ig) superfamily. CD244 is a cell surface protein expressed by NK cells, T cells, monocytes, eosinophils, myeloid-derived suppressor cells, and dendritic cells. CD244 binds to the ligand CD48 on adjacent cells and transmits stimulatory or inhibitory signals that regulate immune function. In-depth studies reported that CD244 functions in many immune-related diseases, such as autoimmune diseases, infectious diseases, and cancers, and its action is essential for the onset and progression of these diseases. The discovery of these essential roles of CD244 suggests it has potential as a prognostic indicator or therapeutic target. This review describes the molecular structure and function of CD244 and its roles in various immune cells and immune-related diseases.

New twists in humoral immune regulation by SLAM family receptors

SLAM family receptors are involved in humoral immune regulation. In this issue of JEM, Zhong et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20200756) provide evidence that these receptors collectively suppress germinal center reaction but promote production of antigen-specific antibodies.

System-wide hematopoietic and immune signaling aberrations in COVID-19 revealed by deep proteome and phosphoproteome analysis

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has become a global crisis. To gain systems-level insights into its pathogenesis, we compared the blood proteome and phosphoproteome of ICU patients with or without SARS-CoV-2 infection, and healthy control subjects by quantitative mass spectrometry. We find that COVID-19 is marked with hyperactive T cell and B cell signaling, compromised innate immune response, and dysregulated inflammation, coagulation, metabolism, RNA splicing, transcription and translation pathways. SARS-CoV-2 infection causes global reprogramming of the kinome and kinase-substrate network, resulting in defective antiviral defense via the CK2-OPN-IL-12/IFN-I axis, lymphocyte cell death via aberrant JAK/STAT signaling, and inactivation of innate immune cells via inhibitory SIRPA, SIGLEC and SLAM family receptor signaling. Our work identifies CK2, SYK, JAK3, TYK2 and IL-12 as potential targets for immunomodulatory treatment of severe COVID-19 and provides a valuable approach and resource for deciphering the mechanism of pathogen-host interactions.

Immune Functions of Signaling Lymphocytic Activation Molecule Family Molecules in Multiple Myeloma

The signaling lymphocytic activation molecule (SLAM) family receptors are expressed on various immune cells and malignant plasma cells in multiple myeloma (MM) patients. In immune cells, most SLAM family molecules bind to themselves to transmit co-stimulatory signals through the recruiting adaptor proteins SLAM-associated protein (SAP) or Ewing’s sarcoma-associated transcript 2 (EAT-2), which target immunoreceptor tyrosine-based switch motifs in the cytoplasmic regions of the receptors. Notably, SLAMF2, SLAMF3, SLAMF6, and SLAMF7 are strongly and constitutively expressed on MM cells that do not express the adaptor proteins SAP and EAT-2. This review summarizes recent studies on the expression and biological functions of SLAM family receptors during the malignant progression of MM and the resulting preclinical and clinical research involving four SLAM family receptors. A better understanding of the relationship between SLAM family receptors and MM disease progression may lead to the development of novel immunotherapies for relapse prevention.

SLAM family receptors control pro-survival effectors in germinal center B cells to promote humoral immunity

Expression of the signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) is critical for the germinal center (GC) reaction and T cell–dependent antibody production. However, when SAP is expressed normally, the role of the associated SLAM family receptors (SFRs) in these processes is nebulous. Herein, we established that in the presence of SAP, SFRs suppressed the expansion of the GC reaction but facilitated the generation of antigen-specific B cells and antibodies. SFRs favored the generation of antigen-reactive B cells and antibodies by boosting expression of pro-survival effectors, such as the B cell antigen receptor (BCR) and Bcl-2, in activated GC B cells. The effects of SFRs on the GC reaction and T cell–dependent antibody production necessitated expression of multiple SFRs, both in T cells and in B cells. Hence, while in the presence of SAP, SFRs inhibit the GC reaction, they are critical for the induction of T cell–mediated humoral immunity by enhancing expression of pro-survival effectors in GC B cells.

Novel Approaches to Improve Myeloma Cell Killing by Monoclonal Antibodies

The monoclonal antibodies (mAbs) have significantly changed the treatment of multiple myeloma (MM) patients. However, despite their introduction, MM remains an incurable disease. The mAbs currently used for MM treatment were developed with different mechanisms of action able to target antigens, such as cluster of differentiation 38 (CD38) and SLAM family member 7 (SLAMF7) expressed by both, MM cells and the immune microenvironment cells. In this review, we focused on the mechanisms of action of the main mAbs approved for the therapy of MM, and on the possible novel approaches to improve MM cell killing by mAbs. Actually, the combination of anti-CD38 or anti-SLAMF7 mAbs with the immunomodulatory drugs significantly improved the clinical effect in MM patients. On the other hand, pre-clinical evidence indicates that different approaches may increase the efficacy of mAbs. The use of trans-retinoic acid, the cyclophosphamide or the combination of anti-CD47 and anti-CD137 mAbs have given the rationale to design these types of combinations therapies in MM patients in the future. In conclusion, a better understanding of the mechanism of action of the mAbs will allow us to develop novel therapeutic approaches to improve their response rate and to overcome their resistance in MM patients.