Citations

Abstract In the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment. However, when CD19+ cell lines were pretreated with tafasitamab overnight and the unbound antibody was subsequently removed from the culture, CART19 function was not affected. In preclinical in vivo models, tafasitamab pretreatment demonstrated reduced incidence and severity of cytokine release syndrome and exhibited superior antitumor effects and overall survival compared with CART19 alone. This was associated with transient CD19 occupancy with tafasitamab, which in turn resulted in the inhibition of CART19 overactivation, leading to diminished CAR T apoptosis and pyroptosis of tumor cells.

Nonalcoholic fatty liver disease (NAFLD) represents a significant health threat worldwide. The aging population and a rise in metabolic syndrome in Asia might influence the epidemiology of NAFLD among the elderly. However, there is a lack of understanding of the burden and recommendations for NAFLD in this group. Our study sought to investigate the trends in the NAFLD burden among the elderly in the Asia-Pacific region. We employed data from the Global Burden of Disease 2019 study for an in-depth analysis of the prevalence and disability-adjusted life years (DALYs) along with age-standardized rate (ASR) associated with NAFLD in elderly populations (age 65–89 years) across the Asia-Pacific region, including the Southeast Asia (SEA) and Western Pacific (WP) regions, from 2010 to 2019. This study also examined the trends and disparities in NAFLD burden across different nations and sexes. In 2019, there were over 120 million cases of NAFLD in the elderly in the Asia-Pacific region. The ASR of prevalence was higher in SEA compared to WP (36,995.37 vs. 32,821.78 per 100,000). ASR of prevalence increased with annual percentage change (APC) +0.95% in the WP while it increased by +0.87% in SEA. During the study period, the ASR of DALYs decreased in SEA (APC −0.41%) but remained stable in the WP region. The burden of NAFLD in the elderly population in Asia-Pacific has increased, underscoring the timely intervention to tackle this high and rising burden.

AbstractBackground and AimEarly‐onset colorectal cancer (CRC) is a growing global health concern, especially in the Asia‐Pacific region. However, comprehensive research on this topic from the region is lacking. Our study aims to investigate trends in early‐onset CRC in Asia over 10 years, filling this research gap.MethodsThis study utilized data from the Global Burden of Disease Study 2019 to assess temporal trends in early‐onset CRC in the Asia‐Pacific. The analysis included estimating annual frequencies and age‐standardized rates (ASRs) of early‐onset CRC incidence, death, and disability‐adjusted life‐years (DALYs) by gender.ResultsThe incidence of early‐onset CRC significantly increased in both regions with higher increase and in the Western Pacific region. Notable increases were observed among males in the Western Pacific and females in Southeast Asia (SEA). Mortality rates remained stable in the Western Pacific but increased by 10.6% in SEA, especially among females. DALYs due to CRC also increased significantly in SEA, with a greater rise among females. The Western Pacific had the highest CRC incidence, and in SEA, the mortality rate was higher in females than males.ConclusionsOur study reveals a substantial increase in early‐onset CRC in the Asia‐Pacific underscoring the urgency for effective interventions. Thus, a comprehensive approach comprising controlled risk reduction, health promotion to heightened disease awareness, and implementation of effective screening strategies should be executed timely to mitigate the burden of early‐onset CRC.

Abstract At the terminal position of many glycan chains are unique sugars known as sialic acids. Sialic acids bind sialic acid immunoglobin-like lectins (Siglecs). Our lab is interested in the role of CD22 (Siglec-2), which binds to α2,6-linked sialic acid generated by ST6GalI. CD22 can associate with itself or other molecules on the same cells in a “cis” configuration or bind in “trans” with ligands on other cells. CD22 contains four ITIMs within its cytoplasmic tail and is primarily known to function as an inhibitory co-receptor of the B cell receptor (BCR). CD22-ligand interactions restrain CD22 and BCR association which dampens BCR signaling. While CD22 is usually characterized as a B cell specific protein, we found that CD22 is highly expressed in hybrid macrophages (CD11b+ CD11c+ F4/80+) and expression decreases with activation, implying that CD22 may modulate myeloid cell responses. Using novel macrophage and dendritic cell-specific CD22 cKO mouse models, we will explore how CD22 impacts myeloid cell activation. We propose that CD22 impacts myeloid cell function and modulating this interaction may improve immune responses.

Abstract Inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) affects between 1–3 million people in the United States and costs an estimated $11–28 billion in national healthcare costs. Patients present with symptoms including diarrhea, rectal bleeding, and fatigue. Characterization of molecules that regulate IBD is critical in understanding pathogenesis. ST8Sia6 is a sialic acid transferase that adds terminal a2,8 disialic acids to cell surface glycoproteins, and we have found that ST8Sia6 knockout (KO) mice exhibit increased spontaneous small bowel (SB) lamina propria CD4 TH1 polarization, increased inflammatory cytokine production, decreased IgA class switching of SB plasma cells, and alterations of the SB innate lymphoid cells, indicative of gut inflammation. Moreover, adult ST8Sia6 KO mice have shortened small and large bowels, likely due to baseline inflammation. These mice do not exhibit overt baseline symptoms, but ST8Sia6 KO mice exhibit increased weight loss and decreased survival when challenged with dextran sodium sulfate (DSS)-induced colitis, which was also enhanced when co-housed with wildtype (WT) mice. DSS-challenged ST8Sia6 KO mice exhibit increased histological damage and immune infiltration of the gut as compared to WT controls. Accelerated DSS-induced colitis is also observed when ST8Sia6-deficient bone marrow is transplanted into WT recipients, indicating that the effect is mediated specifically by immune cells. This data demonstrates a role for ST8Sia6 in regulating the host immune response to IBD, and further elucidating this role will aid in developing a mechanistic understanding of IBD pathogenesis and in understanding potential immunotherapies for the disease. R01CA243545, 5T32DK124190-03

Abstract Histone acetyltransferases (HATs) and histone deacetylases (HDACs) facilitate addition or removal of various acyl groups from lysine residues, including acetylation (KAc) and crotonylation (KCr). Recently, mutations in p300 and CBP were identified that abrogate their function as an acetyltransferase but not the ability to mediate crotonylation. These mutants can activate transcription independent of their ability to acetylate histones, demonstrating that crotonylation can also lead to transcriptional activation. The Class I deacetylases HDAC1, HDAC2, and HDAC3 have been shown to have both decrotonylase and deacetylase activity, but the relative importance of each function in T cells is not known. Genetic knockout of HDAC3 using CD2 icre mice results in a severe block in T cell development and spontaneous development of severe colitis. Examination of HDAC3 cKO mice has shown an aberrant ratio of Treg:Th17 cells within the gut, driving inflammation and loss of mucosal barrier integrity. Our lab has also determined that HDAC3 is required for at least three aspects of T cell development: CD4+ CD8+ (DP) cell survival, positive selection, and CD4+ lineage development. Recently, a mutation was identified in either HDAC1 or HDAC3 that eradicated deacetylase activity but retained decrotonylase activity (“VRPP”). Through this mutation we were able to generate a novel mouse model with Cre-mediated deletion of endogenous HDAC3 and linked re-expression of HDAC3 VRPP. Strikingly, this mouse does not develop colitis, although T cell development is still impaired. Thus, HDAC3 decrotonylase activity alone is sufficient to impede the IBD phenotype. Support by grants from National Institute of Allergy and Infectious Diseases (R01 AI150100)

Abstract In this study, we leveraged immunomodulatory Siglec-sialic acid interactions to protect beta-cells against autoimmune rejection in Type 1 Diabetes (T1D). Our lab previously demonstrated that the sialyltransferase ST8Sia6 generates ligands that bind the Siglec-E receptor expressed on murine islet-resident macrophages. Here, mice were engineered to express ST8Sia6 in beta cells (βST mice), backcrossed to the non-obese diabetic (NOD) mouse model of T1D, and followed for disease. 60% of female littermates spontaneously developed disease by 300 days, compared to only 6% in female βST mice. Histologic analysis of pancreas sections from non-diabetic βST and littermate mice suggested a similar degree of immune infiltration in early life, but drastically reduced insulitis only in βST mice at later timepoints. This was not due to an absence of autoreactive T cells, as an anti-PD-L1 challenge resulted in similarly rapid induction of disease in both βST and littermate mice. Our genetic model allows for temporal control of ST8Sia6 expression in βST mice using the tet-off system. Treating our mice with doxycycline at 20 weeks of age resulted in persistent protection compared to age matched littermates, while the same treatment at 8 weeks of age led to similar incidence of diabetes between βST mice and littermate controls. Flow cytometric analysis of islet infiltrating immune cells from euglycemic mice at 14 weeks of age demonstrated reductions in short-lived effector CD8 T cells and increased thymically derived Tregs in βST mice compared to littermate controls. These results highlight the therapeutic potential of sialyltransferase mediated immune regulation and present a potential path toward improved curative approaches for T1D. Supported by grants from NIH (5R21AI135858-02, 1F30DK127564)

Abstract The lifetime risk for colorectal cancer in the United States is approximately 4%. Individuals with Inflammatory Bowel Disease, including Ulcerative Colitis and Crohn’s Disease, have a substantially increased risk of developing colorectal cancer. The mechanisms for accelerated tumorigenesis due to enhanced inflammation are not fully characterized. Siglecs (sialic acid immunoglobulin lectin-like proteins) are a family of inhibitory receptors that are negative regulators of the immune response. Siglec-E is an inhibitory receptor that is expressed by innate immune cells, including monocytes, macrophages, neutrophils and dendritic cells. Interestingly, mice deficient in Siglec-E have accelerated development of tumors and reduced survival in a spontaneous mouse model of colorectal cancer (TS4-cre LSL-KRasG12D APClox468/wt). While tumors develop at approximately six months in mice with Siglec-E, tumors develop at approximately two months in Siglec-E knockout mice. Initial results indicate that Siglec-E knockout mice also have accelerated gut inflammation using the DSS colitis model as compared to WT mice. Current studies are examining inflammation that develops during tumorigenesis in Siglec-E knockout mice. Center for Biomedical Discovery NIH R01 CA243545-01A1 to VSS Mayo Clinic Graduate School of Biomedical Sciences Deans fellowship: Initiative for maximizing student development (IMSD) R25 GM055252-26 Doyon Foundation