- |||||||||| Review, Journal: Histomorphological patterns of regional lymph nodes in COVID-19 lungs (Pubmed Central) - Mar 11, 2021
Taken together, our findings imply a dysregulated immune response in lethal COVID-19. The absence/hypoplasia of germinal centers and increased presence of plasmablasts implies a transient B‑cell response, implying an impaired development of long-term immunity against SARS-CoV‑2 in such occasions.
- |||||||||| Journal: Pregnancy Gestation Impacts on HIV-1-Specific Granzyme B Response and Central Memory CD4 T Cells. (Pubmed Central) - Mar 9, 2021
Gag and Nef HIV-1-specific responses diverge with pregnancy time-point, coinciding with relevant T-cell phenotype, and gestation associated immunological adaptations. Decreased IL-10 Nef and both increased granzyme B Gag response and central memory CD4 T cells implies that amplified antigen production is occurring, which suggests a period of compromised HIV-1 control in pregnancy.
- |||||||||| Journal: NKG2C NK Cells Regulate the Expansion of Cytomegalovirus-Specific CD8 T Cells. (Pubmed Central) - Mar 9, 2021
Moreover, intracellular levels of caspase 3/7 were increased in HLA-E Jurkat cells compared with HLA-E Jurkat cells, consistent with higher rates of apoptosis in HLA-E T cells in the presence of NKG2C NK cells. Our data show that NKG2C NK cells interact with HLA-E CD8 T cells, which may negatively regulate the expansion of CMV-specific CD8 T cells upon activation.
- |||||||||| Journal, IO biomarker: Immunological potential of tertiary lymphoid structures surrounding the primary tumor in gastric cancer. (Pubmed Central) - Mar 9, 2021
The majority of tumor‑infiltrating B cells in gastric cancer exist in the form of TLSs around the tumor and have been antigen‑sensitized and differentiated, and proliferated in TLSs but not in the lymph nodes. In addition, B cells in TLSs might primarily function as antigen‑presenting cells and be associated with the induction of cytotoxic T cells.
- |||||||||| Herceptin (trastuzumab) / Roche
Journal: Downregulated ATP6V1B1 expression acidifies the intracellular environment of cancer cells leading to resistance to antibody-dependent cellular cytotoxicity. (Pubmed Central) - Mar 9, 2021
Among several mechanisms for the resistance of human epidermal growth factor receptor 2-overexpressing (HER2 +) cancer cells to trastuzumab, little is known regarding the mechanism underlying the resistance to trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC)...An analysis of granzyme dynamics during the ADCC reaction in cancer cells revealed that granzymes degraded intracellularly in the control SKBR3 and JIMT-1 cells and accumulated in ATP6V1B1-knockout cells, but were not cytotoxic. These findings suggest that decreased vacuolar ATPase activity alters the cytoplasmic pH of cancer cells to create an environment that is less suitable for granzyme bioactivity, which adversely affects the induction of apoptosis of cancer cells by NK cells.
- |||||||||| Tecentriq (atezolizumab) / Roche
Journal: Atezolizumab and granzyme B as immunotoxin against PD-L1 antigen; an insilico study. (Pubmed Central) - Mar 9, 2021
Consequently, based on this approach we could introduce a capable immunotoxin which specifically targeting PD-L1 in an accurate orientation and initiates cancer cell destruction by its toxin domain. The online version contains supplementary material available at 10.1007/s40203-021-00076-z.
- |||||||||| Journal: CD73 Ectonucleotidase Restrains CD8+ T Cell Metabolic Fitness and Anti-tumoral Activity. (Pubmed Central) - Mar 9, 2021
In agreement, when adoptively transferred, antigen-specific CD73-deficient CD8+ T cells were more effective in reducing the tumor burden in B16.OVA melanoma-bearing mice and presented lower levels of exhaustion markers than wild type cells. All these data suggest an autocrine effect of CD73-mediated adenosine production, limiting differentiation and cytotoxic T cells' metabolic fitness.
- |||||||||| Review, Journal: TRPML Cation Channels in Inflammation and Immunity. (Pubmed Central) - Mar 5, 2021
Advances: Examples of recently established roles of TRPML channels in immune system function and immune response include the TRPML1-mediated modulation of secretory lysosomes, granzyme B content, and tuning of effector function in NK cells, TRPML1-dependent directional dendritic cell (DC) migration and DC chemotaxis, and the role of TRPML2 in chemokine release from LPS-stimulated macrophages. Outlook: Although our understanding of the functional roles of TRPML channels in inflammation and immunity is still in its infancy, a few interesting findings have been made in the past years, encouraging further and more detailed work on the role of TRPMLs, e.g., in intracellular trafficking and release of chemokines, cytokines, or granzyme B, or in phagocytosis and bacterial toxin and virus trafficking through the endolysosomal machinery.
- |||||||||| Journal: Retrograde migration supplies resident memory T cells to lung-draining LN after influenza infection. (Pubmed Central) - Mar 3, 2021
Investigations of bystander infection or removal of the TCR from established memory cells revealed that the induction of the TRM phenotype was dependent on antigen recognition; however, maintenance was independent. Thus, local lung infection induces CD8+ T cells with a TRM phenotype that nevertheless undergo retrograde migration, yet remain durably committed to the residency program within the draining LN, where they provide longer-lived regional memory while chronicling previous upstream antigen experiences.
- |||||||||| chloroquine phosphate / Generic mfg.
Journal, PD(L)-1 Biomarker, IO biomarker: Blocking drug-induced autophagy with chloroquine in HCT-116 colon cancer cells enhances DC maturation and T cell responses induced by tumor cell lysate. (Pubmed Central) - Feb 26, 2021
Furthermore, the decreased expression of genes related to metastasis and tumor progression (BNIP3, BNIP3L, FOSL2, HES1, LAMB3, LOXL2, NDRG1, P4HA1, PIK3R2) was noted. The combination of 5-FU and CQ increases the ability of tumor cells to drive DC maturation and enhances the ability of DCs to stimulate T cell responses.
- |||||||||| Review, Journal: The Role of T Cells in the Pathogenesis of Vitiligo-A Review of the Current State-Of-The-Art. (Pubmed Central) - Feb 26, 2021
The findings above, as well as their reference to the pathogenesis of autoimmune skin diseases will have a considerable influence on the development of new therapeutic strategies in the near future. This article presents an up-to-date review of information regarding the role of T cells in the development and progression of vitiligo.
- |||||||||| Journal, IO biomarker: Granzyme B PET Imaging of the Innate Immune Response. (Pubmed Central) - Feb 26, 2021
These findings support the use of granzyme B PET for imaging innate immunity. In certain clinical contexts, the use of GZP PET imaging may be superior to currently available agents, and we therefore suggest further preclinical studies with the ultimate goal of translation to clinical use.
- |||||||||| Rituxan (rituximab) / Biogen, Zenyaku Kogyo, Roche
Clinical, Journal, PD(L)-1 Biomarker, IO biomarker: Vincristine upregulates PD-L1 and increases the efficacy of PD-L1 blockade therapy in diffuse large B-cell lymphoma. (Pubmed Central) - Feb 25, 2021
In certain clinical contexts, the use of GZP PET imaging may be superior to currently available agents, and we therefore suggest further preclinical studies with the ultimate goal of translation to clinical use. VCR upregulated PD-L1 expression in DLBCL cells partially by promoting the p-STAT3; VCR combined with PD-L1 Ab activated effector T cells and increased the antitumor immune response in vitro and in vivo.
- |||||||||| Zyclara (imiquimod) / Mochida, Mylan, Bausch Health
Preclinical, Journal: Immunological Memory in Imiquimod-Induced Murine Model of Psoriasiform Dermatitis. (Pubmed Central) - Feb 24, 2021
Importantly, these CD49a Trm cells showed significantly higher levels of granzyme B (GzmB) production compared to acute disease, suggesting a potential role of CD49a Trm cells for psoriatic re-occurrence in resolved patients. Better understanding of epidermal CD49a Trm cell activity is necessary for development of advanced treatment strategies for psoriasis to permit long-term, continuous disease control.
- |||||||||| Preclinical, Journal: Indirect Impact of PD-1/PD-L1 Blockade on a Murine Model of NK Cell Exhaustion. (Pubmed Central) - Feb 20, 2021
These data suggest a bystander effect of anti-PD1 on NK cells, resulting from the global competition that exists between NK and CD8 T cells for IL-2 as a key regulator of these cells' activation. Thus, achieving an equilibrium between these immune cells might be important to accomplish long-term efficacy during anti-PD-1/IL-2 therapy.
- |||||||||| Journal: Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis. (Pubmed Central) - Feb 18, 2021
However, these mice established fewer CD8 tissue-resident memory T (T) cells and were more likely to experience reactivation of viral RNA synthesis late after infection. Therefore, IFN-γ suppresses the local development of granzyme B-expressing CD8 T cells and slows viral RNA clearance but promotes CD8 T cell establishment.
- |||||||||| Clinical, Journal: Mucosal-Associated Invariant T (MAIT) Cells Are Highly Activated and Functionally Impaired in COVID-19 Patients. (Pubmed Central) - Feb 18, 2021
Upon MAIT cell-specific in vitro stimulation, MAIT cells however failed to upregulate expression of the cytokines IL-17A and TNFα, as well as cytolytic proteins, that is, granzyme B and perforin. Thus, our data point towards an altered cytokine expression profile alongside an impaired antibacterial and antiviral function of MAIT cells in COVID-19 and thereby contribute to the understanding of COVID-19 immunopathogenesis.
- |||||||||| Journal, IO biomarker: Protein Kinase C-η Deficiency Does Not Impair Antiviral Immunity and CD8 T Cell Activation. (Pubmed Central) - Feb 17, 2021
In addition, purified Prkch mouse CD8 T cells as well as PRKCH knockdown human CD8 T cells displayed intact, or even enhanced, T cell activation in vitro as measured by proliferation and expression of granzyme B and IFN-γ. Thus, global PKCη deletion does not impair overall CD8 T cell-mediated immunity, including antiviral immunity, implying that selective pharmacological PKCη inhibition could be safely used in vivo to inhibit undesired contact-dependent suppression by Tregs and, thus, enhance tumor-specific and, likely, virus-specific immunity.
- |||||||||| Jakafi oral (ruxolitinib) / Novartis, Incyte
Journal: Analysis of ex vivo expanded and activated clinical-grade human NK cells after cryopreservation. (Pubmed Central) - Feb 17, 2021
Thus, global PKCη deletion does not impair overall CD8 T cell-mediated immunity, including antiviral immunity, implying that selective pharmacological PKCη inhibition could be safely used in vivo to inhibit undesired contact-dependent suppression by Tregs and, thus, enhance tumor-specific and, likely, virus-specific immunity. Usage of C/T EA NK cells may be an option to provide serial "boost" NK cell infusions from a single apheresis to maximize NK cell persistence and potentially improve NK-induced responses to refractory cancer.
- |||||||||| Journal: Evaluation of expression of common genes in the intestine and peripheral blood mononuclear cells (PBMC) associated with celiac disease. (Pubmed Central) - Feb 17, 2021
Among 20 CD genes as hub and bottleneck nodes, there were 7 genes with common expression in blood and intestinal tissue (C-X-C motif chemokine 11(CXCL11), granzyme B (GZMB), interleukin 15(IL-15), interleukin 17(IL-17A), interleukin 23(IL-23A), t-box transcription factor 21(TBX21), and tumor necrosis factor alpha-induced protein 3(TNFAIP3)). The enriched biological process related to the central nodes of celiac network indicated that most of hub-bottleneck genes are the well-known ones involved in different types of autoimmune and inflammatory diseases.
- |||||||||| [VIRTUAL] Out With the Old, In With the New WHO: How the WHO Breast Tumors 5th Edition Could Change Your Diagnosis - D'Alfonso () - Feb 15, 2021 - Abstract #USCAP2021USCAP_1003;
A TNM staging system has been proposed that is based on extent of tumor infiltration through the capsule, lymph nodes involved, and the presence or absence of metastatic disease, similar to a system used for solid tumors: T Stage: T1 Tumor confined to luminal side of capsule T2 Superficial infiltration of capsule T3 Deep infiltration of capsule T4 Infiltration through capsule N Stage: N0 No lymph nodes involved N1 One positive node N2 Multiple positive nodes M Stage: M0 No distant spread M1 Distant spread Patients with BIA-ALCL have an exceptionally good prognosis and patients with disease localized to the capsule are adequately treated with implant removal and capsulectomy alone. Patients with more advanced disease that show chest wall extension and/or regional lymph node involvement are offered cytotoxic chemotherapy and/or radiation.
- |||||||||| Preclinical, Journal, IO biomarker: Studying the biology of cytotoxic T lymphocytes in vivo with a fluorescent granzyme B-mTFP knock-in mouse. (Pubmed Central) - Feb 13, 2021
Expression of the fluorescent fusion protein allows quantitative analyses of cytotoxic granule maturation, transport and fusion in vitro with super-resolution imaging techniques, and two-photon microscopy in living knock-ins enables the visualization of tissue rejection through individual target cell-killing events in vivo. Thus, the new mouse line is an ideal tool to study cytotoxic T lymphocyte biology and to optimize personalized immunotherapy in cancer treatment.
- |||||||||| Thalomid (thalidomide) / Fujimoto, BMS
Clinical, Journal: Synergistic Mechanism of Interferon alpha-1b, Interleukin-2 and Thalidomide for Immune Regulation in Patients with Acute Myeloid Leukemia (Pubmed Central) - Feb 9, 2021
This SSL-induced cSCC model in inbred mice will facilitate future studies investigating anti-tumor T cell responses and genes influencing tumor formation and response to therapy. The ITI regimen can raise the ratio of CD4/CD8 T cells and the percentage of natural killer cells, also, can enhance the generation of perforin and granzyme B and the concentration of IFN-γ as well as inhibit the generation of VEGF, suggesting that these activities may enhance the antitumour capacity of patients with AML.
- |||||||||| Imunorix (pidotimod) / Almirall
Preclinical, Journal: Pidotimod enhanced the anti-growth effect of cisplatin on lung cancer in mice via promoting anti-tumor immune response. (Pubmed Central) - Feb 5, 2021
With further exploration, we found that Pidotimod enhanced the anti-growth effect of cisplatin on LLC via promoting anti-tumor response, such as increased infiltration of dendrite cells (DCs) and CD8 T cells as well as enhancement of IFN-γ and Granzyme B expression. In summary, Pidotimod affects the anti-tumor function of cisplatin via promoting anti-tumor immune response and these findings provide a novel approach for the development of therapeutic strategies for lung cancer.
- |||||||||| [VIRTUAL] Alterations in STAT Signaling Dysregulate CD8 T Cell Activation () - Feb 3, 2021 - Abstract #AAAAI2021AAAAI_1153;
IL-2, IFN-gamma). Conclusions Immunometabolic dysregulation as a result of altered STAT signaling affects both T cell phenotype and function, yielding potential novel therapeutic targets for our rare patients as well as deeper understanding of these fundamental cytokine signaling pathways . We will pursue these hypotheses in mouse models and in vitro human cellular studies.
- |||||||||| Journal: Tissue-resident T cell derived cytokines eliminate herpes simplex virus-2 infected cells. (Pubmed Central) - Feb 3, 2021
A sufficiently high density of HSV-2 specific TRM predicted rapid elimination of infected cells, but our data suggest that such TRM densities are relatively uncommon in infected tissues. At lower, more commonly observed TRM densities, TRM must initiate a rapidly diffusing, polyfunctional cytokine response with activation of bystander T cells in order to eliminate a majority of infected cells and eradicate briskly spreading HSV-2 infection.
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