bluuebunny/crossref_metadata_2025_split huggingface dataset:
Caloric-restriction maintains tumor immunity and CD4 T cells priming during aging: role of an inflammatory DC population (P2175)
Authors: Ruby Carl , Farazi Michelle , Goldufsky Josef , Cohn Zachary , Linnane Stephanie , Nguyen Justine , Lukaesko Lisa , Weinberg Andrew 
Published: January 2023

Abstract
Immune responses progressively wane during aging, posing significant challenges to the protection and treatment of cancer. We previously demonstrated that in the context of OX40 costimulation older animals exhibited impaired anti-tumor immune responses and diminished CD4 T cell effector differentiation. We hypothesized that anti-tumor immune responses could be maintained during aging through caloric restriction (CR) or dietary supplementation with resveratrol (RES), a CR mimetic. Mice were placed on either a restricted diet or a RES-formulated diet starting between 4 and 6 months of age and continued until mice reached 12 months of age. Tumor immune responses were assessed by challenging with either sarcoma or breast tumor cells followed by agonist OX40 treatment. Our results show CR, but not RES, maintained OX40-mediated anti-tumor immunity, during aging. In addition, CR maintained tumor-specific CD4 T cell activation in aged mice. This observed effect of CR on T cell activation, lead to an assessment of DCs. We found that the accumulation of an inflammatory DC subset (CD11c+CD11b+Ly6C+), critical for the activation of CD4 T cells, was significantly decreased in the LNs of older control mice compared to young mice. In contrast, CR aged mice had more inflammatory DCs in the priming LNs compared to aged controls. Thus, CR appears to maintain immunological fitness of a DC subset during aging that is critical for antigen-specific CD4 T cell activation and tumor immunity.
Smurf2 mediates ubiquitination and degradation of YY1 to suppress B-cell proliferation and lymphomagenesis (P2181)
Authors: Gerstein Rachel , Ramkumar Charusheila , Cui Hang , Kong Yahui , Jones Stephen , Zhang Hong 
Published: January 2023

Abstract
Current treatment of diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin’s lymphoma, has improved patient survival significantly. However, 40-50% of DLBCL patients still die from this disease. There is a critical need to better understand the specific molecular pathways that are perturbed in DLBCL for the development of new therapeutic approaches. Using a mouse model deficient in the E3 ubiquitin ligase Smurf2, we show that Smurf2 deficiency increases the susceptibility of these mice to spontaneous B-cell lymphomagenesis. Lymphomas developed in Smurf2-deficient mice resemble human DLBCL with molecular features of germinal center B cells. We discover that Smurf2 mediates ubiquitination and degradation of YY1, a key germinal center transcription factor. Importantly, loss of Smurf2 enhances YY1-mediated transactivation of c-Myc and B-cell proliferation. Furthermore, we find that expression of Smurf2 is significantly decreased in primary human DLBCL samples compared to normal B cells. Importantly, low levels of Smurf2 expression correlate with poor survival prognosis in DLBCL patients. The Smurf2-YY1-c-Myc regulatory axis represents a novel pathway perturbed in DLBCL that suppresses B-cell proliferation and lymphomagenesis, and identifies Smurf2 as a new therapeutic paradigm for DLBCL.
Autophagy in tumor cells and the host STING pathway are critical for innate immune sensing of tumors and bridging to an adaptive immune response (P2183)
Authors: Woo Seng-Ryong , Fuertes Mercedes , Furdyna Michael , Leung Michael , Duggan Ryan , Gajewski Thomas 
Published: January 2023

Abstract
Spontaneous T cell responses against tumors occur frequently. However, the mechanisms by which innate immune responses become induced in response to cancer, and how they can bridge to T cell priming against tumor antigens, have remained poorly defined. We recently reported that host type I IFN signals are required for a spontaneous T cell response against tumors. In the current work, we have mapped the sensing mechanism to one involving STING/TBK1/IRF3 which drives IFN-β transcription by host APCs. The tumor-derived ligand that triggers this pathway appears to be DNA. Using the DNA-specific dye DRAQ5 or EDU labeling, we demonstrated transfer of tumor DNA to host APCs via single cell ImageStream analysis; this was confirmed using PCR specific for tumor DNA. This was associated with IFN-β mRNA induction and nuclear translocation of IRF-3, which were dependent upon host STING. We hypothesized that autophagosome provide a mechanism for delivery of protected tumor DNA into APCs. By inhibition of tumor cell autophagy using the chemical 3-MA, or shRNA silencing of Becn or ATG5, we found marked reduction in the induction of host IFN-β production and spontaneous T cell responses in vivo. Our data suggest that tumor cell autophagy is required for optimal T cell priming against tumor antigens in vivo, that occurs through DNA-mediated activation of host IFN-β production via a STING-dependent pathway.
IL-17D, natural killer cells, and macrophages collaborate to promote tumor rejection (P2097)
Authors: Bui Jack , O'Sullivan Timothy , Saddawi-Konefka Robert , Gross Emilie 
Published: January 2023

Abstract
The process of cancer immunoediting generates a repertoire of cancer cells that can persist in immune competent hosts. In its most complex form, this process begins with the elimination of highly immunogenic unedited tumor cells followed by the eventual escape of less immunogenic, edited cells. However, it is not known whether editing can also change the global gene expression profile of developing tumor cells. Here we show using a gene microarray study that the novel cytokine interleukin 17D (IL-17D) is highly expressed in certain unedited but not edited mouse tumor cell lines or certain human tumors. Moreover, forced expression of IL-17D in edited tumor cells induced rejection by stimulating monocyte chemotactic protein 1 (MCP-1, aka CCL2) production from tumor endothelial cells leading to the recruitment of natural killer (NK) cells. We go on to show that NK cells can promote the accumulation of M1-type macrophages. Altogether, these results identify IL-17D as a novel cytokine and describe one mechanism by which IL-17D can induce tumor rejection.
Human multi-cancer gene expression analysis defines an inflammatory cancer-associated molecular pattern with prognostic significance (P2209)
Authors: Rachidi Saleh , Qin Tingting , Sun Shaoli , Zheng Jim , Li Zihai 
Published: January 2023

Abstract
Chronic inflammation is a hallmark of cancer. We propose that a “signature” of dysregulated inflammatory molecules exists across multiple cancer types. Genome-wide cDNA expression data was analyzed for 221 normal and 324 cancer specimens in 7 cancer types: breast, prostate, lung, colon, gastric, oral and pancreatic. 44 elevated and 52 repressed genes were identified and protein expression was confirmed by immunohistochemistry for some of these genes. This “Inflammatory Cancer-Associated Molecular Pattern” includes proteins whose roles in cancer are known and others (BST2, TNFAIP6, TNFSF4 and LEAP2) whose functions are yet to be appreciated. Clinical analysis in colon and ovarian cancer patients showed strong associations with tumor grade, stage and/or survival. In ovarian cancer, 18 genes predicted overall survival and 15 genes predicted recurrence. In colon cancer, 13 and 17 genes predicted 5-year overall and relapse-free survival, respectively. In both diseases, better prognosis correlated with high CXCL13 and lower level of GREM1, LOX, TNFAIP6, CD36, and EDNRA. An “Inflammatory Gene Integrated Score” was further developed from these genes, which also predicted survival in an independent cohort of ovarian cancer patients. This work defines an inflammatory signature shared by seven epithelial cancer types, which not only has significant biological implications, but also may serve as a novel biomarker for prognostication and individualized treatment of cancer.
The roles of tumor associated macrophages and interferon gamma in immune surveillance in CNS lymphoma (P2211)
Authors: Gao Hua-Xin , Wong Valerie , Chen Lingjing , Locksley Richard , Lowell Clifford , Rubenstein James 
Published: January 2023

Abstract
The distinctive roles of macrophages in cancer are believed to reflect selective M1 or M2 states of differentiation. Central nervous system lymphomas (CNSL) are aggressive tumors with poor prognosis. We generated murine CNSL models to elucidate the role of the immune microenvironment, especially macrophages, in this disorder. We determined that the majority of tumor-associated macrophage (TAM) expressed the mannose receptor CD206, an established M2 marker, and showed phagocytic activity of lymphoma. Surprisingly, this phenotype of TAM was also observed in mice deficient in IL-4, IL-4Ra, IL-10, or STAT6, suggesting that the M2-like feature of TAM was not driven by Th2 pathways. Few TAM were noted to express arginase I, another M2 marker. We also found upregulation of M1 markers MHCII and nitric oxide on TAMs, indicating a M1/M2 intermediate phenotype. CNSL progressed more rapidly In IFNγ-/- Rag-/- mice than in Rag-/- mice. Furthermore, macrophage depletion significantly exacerbated CNSL progression, but failed to do so in IFNγ deficient mice, suggesting that IFNγ-primed macrophage inhibits tumor growth in CNSL. Reduction of macrophage infiltration to tumor site promoted CNSL progression. Distinct from the CD45loCD11blo microglias, TAMs were CD45hiCD11bhi and maintained Ly6C, suggesting a monocytic origin of these cells. Based upon this data we report that CNSL TAMs present both M1 and M2 features and may mediate immune surveillance against lymphoma progression in brain.
Anti-nuclear IgM antibodies protect against lymphoma/lymphocytic leukemia (P2219)
Authors: Jiang Chuancang , Zhao Ming-Lang , Hobbie Kristen , Herbert Ronald , Diaz Marilyn 
Published: January 2023

Abstract
Our previous work showed that AID-deficient MRL/lpr (AID-/-) mice which had high levels of autoreactive IgM experienced a longer lifespan than muS-/-AID-/-MRL/lpr (muS-/-) mice whose B cells did not secrete any antibodies. Histology results indicated that these mice died of Lymphoma/lymphocytic leukemia (LLL). Further studies showed that at 6 months of age, all muS-/- mice developed LLL, while only 24% AID-/- mice had LLL. At 12 months of age, eventually all the mice from both strains developed LLL, but the LLL grade of muS-/- mice was higher than that of AID-/- mice (P = 0.004). When bone marrow cells from AID-/- mice were transferred to muS-/- mice, the mice with successful reconstitution of IgM-secreting B cells (showing high levels of IgM) displayed a lower grade of LLL than both the mice with poor reconstitution of IgM-secreting B cells (showing low levels of IgM) and PBS control mice. In vitro experiments demonstrated that autoreactive IgM-rich serum from AID-/- mice induced apoptosis of lymphoma cell line TK-1 cells, while antibody-absent serum from muS-/- mice did not had the effect. This led to the finding that some anti-nuclear monoclonal IgM antibodies also induced the apoptosis of TK-1 cells. Treatment of p53-/-mice with the mAb reduced the lymphoma grade compared to control mice (P = 0.021). These data demonstrate that anti-nuclear IgM antibodies can protect against LLL, probably through induction of tumor cell apoptosis. (CJ and MZ are equal contributors)
Immune regulation by CD11b+ myeloid cells in the intestine (P3195)
Authors: Murai Masako , Krause Petra , Shui Jr-Wen , Madan Rajat , Karp Christopher , Kronenberg Mitchell 
Published: January 2023

Abstract
We found that a subset of CD11b+ myeloid cells in the intestinal lamina propria constitutively produce IL-10 mRNA, and adoptive transfer of these IL-10 producing cells to recipients helped to maintain Foxp3 expression and the function of Treg. Although much emphasis has been placed on the regulatory role of T cell derived IL-10, our data show that IL-10 synthesis by intestinal myeloid cells has a nonredundant and dramatic effect on maintaining Treg function and preventing T cell-mediated colitis in mice. Here, we further investigate the role of intestinal myeloid cell derived IL-10 in the regulation of gut inflammation. IL-10 producing intestinal myeloid cells expressed higher CD11b, CD11c, F4/80, Gr-1 and CX3CR1 messenger RNA and protein, compared to their non-IL-10 producing intestinal myeloid counterparts. Myeloid cell specific (LysM-Cre driven) IL-10 deficient mice had a similar Treg population in the large intestine compared to controls. C. rodentium infection caused a decrease in the number of Treg in the large intestine, but not in the spleen, and moreover, this defect was more pronounced in mice with a myeloid cell specific IL-10 deficiency. Inflammation in colitis models or following acute infections leads to decreased intestinal Treg. IL-10 producing myeloid cells has a role in maintaining the Treg population in the intestine under inflammatory conditions, as exemplified by C. rodentium infection.
The protective capacity of CD8+ TRM cells in distant skin after cutaneous virus infection (P3201)
Authors: Jiang Xiaodong , Kupper Thomas 
Published: January 2023

Abstract
We have previously shown that repetitive infections of skin at different sites leads to an accumulation of protective T cells that encompass all sites of skin, including those distant from the infected sites. Additional central memory cells also accumulate in lymph nodes. These protective skin homing T cells presumably move out of lymph nodes draining the infected skin, enter the blood stream, and are distributed throughout the body, where they preferentially home to sites that express low constitutive levels of their ligands—E selectin, CCL19, and ICAM-1, all of which are expressed on normal skin. In order to test this theory, we repetitively infected a mouse, and thirty days later we parabiotically joined it to a normal mouse. After four weeks, parabionts were separated, rested for two weeks, and challenged with vaccinia virus (VACV) on distant skin. The previously infected parabiont rapidly cleared VACV infection from distant skin, while the uninfected parabiont, although it contained abundant central memory T cells and antibody, could not efficiently clear infection. This indicates that prior skin infection at different sites in the same organ by the same pathogen multiple times through a subject life leads to subsequent resistance to infection throughout that organ, in a process mediated by skin-resident memory T (TRM) cells generated by multiple infections.
Assessment of interferon responses in intact human placental explants using a novel whole mount immunofluorescence technique (P3205)
Authors: Bushway Meghan , Gerber Scott , Miller Richard , Lord Edith , Murphy Shawn 
Published: January 2023

Abstract
Pro-inflammatory cytokines required for immunity against non-self, such as interferons (IFNs), are expressed at the maternal-fetal interface during normal pregnancy. However, neither the placental cell targets nor the functions of these cytokines have been defined. We hypothesized that semi-allogeneic trophoblast cells (TBCs), which are the only cells derived from the fertilized egg that are in direct contact with maternal tissue, are hypo-responsive to IFNs in order to evade maternal immune recognition. Therefore, we developed a novel whole mount immunofluorescence technique to identify cellular targets of IFN-γ and IFN-α/β by examining expression of phosphorylated STAT-1 (pSTAT-1) in intact human placental explants. Using this technique we were able to identify the major cell populations present in the placental explants, including fetal macrophages and distinct subpopulations of TBCs. Neither the syncytiotrophoblast layer in direct contact with maternal blood, nor the underlying cytotrophoblast cells expressed pSTAT-1 in response to either IFN. In contrast, extravillous trophoblast cells, which are in direct contact with maternal decidual tissue, and fetal macrophages induced strong expression of pSTAT-1 in response to IFNs. The identification of differential IFN responsiveness in distinct human trophoblast cell subpopulations provides important new insights into the roles of IFNs in normal pregnancy and placental pathology and infection.
CD103-CD11b+ mucosal DCs control CD4 T cell responses to bacterial flagellin (P3179)
Authors: Atif Shaikh , McSorley Stephen 
Published: January 2023

Abstract
Toll-like receptor 5 (TLR5) has been widely studied in an inflammatory context, but the effect of TLR5 on the adaptive response to bacterial flagellin has received less attention. Here, we demonstrate that TLR5 expression by DCs allows a 1000-fold enhancement of T cell sensitivity to flagellin, and this enhancement did not require expression of NLRC4 or Myd88. The effect of TLR5 on CD4 T cell sensitivity was independent of the adjuvant effect of flagellin and TLR5 ligation did not alter the sensitivity of OVA-specific T cells. In the spleen, the exquisite T cell sensitivity to flagellin was regulated by CD4-CD8α- dendritic cells and was blocked by a monoclonal antibody to TLR5. In mesenteric lymph nodes, flagellin-specific T cell responses are controlled by a population of CD103-CD11b+ DCs. Thus, TLR5 expression by mucosal and systemic DCs regulates the adaptive immune sensitivity to flagellated pathogens.
Multifunctional and protective memory γδ T cells in intestinal tissues (P3227)
Authors: Sheridan Brian , Romagnoli Pablo , Pham Quynh-Mai , Fu Han-Hsuan , Alonzo III Francis , Schubert Wolf-Deiter , Freitag Nancy , Lefrancois Leo 
Published: January 2023

Abstract
Recently, studies in humans have suggested that γδ T cells may play a role in adaptive immunity. Surprisingly, oral Listeria monocytogenes (Lm) infection of mice induced a unique population of CD27neg CD44high Vγ4+ γδ T cells in the mesenteric lymph nodes (MLN) and lamina propria that was maintained into memory and capable of rapid expansion following secondary infection. Lm-elicited γδ T cells were mobilized into the blood and upregulated the gut homing receptor α4β7 but failed to migrate into the epithelium. The responding γδ T cells produced IL-17A and IFNγ and expressed T-bet and RORγt. Cytokine expression from memory γδ T cells could be induced by MLN from 2 dpi mice and was reduced by depletion of MHC II-expressing cells. Moreover, batf3-/- mice failed to induce γδ T cell expansion suggesting a role for migrant APCs in the activation of Lm-elicited γδ T cells. Interestingly, Lm-elicited memory γδ T cells failed to expand to i.v. Lm infection or oral Salmonella infection suggesting contextual specificity to the priming pathogen. In the absence of αβ T cell control, memory γδ T cells are the predominate source of protection and limit bacterial burden through enhanced expansion and cytokine production. While depletion of αβ T cells or γδ TCR internalization had little effect on protection, coupling treatments completely abrogated protection in intestinal tissues. Thus, γδ T cells are capable of generating a protective mucosal memory population following oral Lm infection.
Life history of cognate antigen exposure indicates skewing of mucosal lymphocyte populations during aging (P3229)
Authors: Vogel Laura , Moitra Samrat , Heidenreich Byron 
Published: January 2023

Abstract
The impact of aging on mucosal immune responses, particularly IgA production, is controversial. Many previous studies haven’t separated effects of the aged microenvironment (i.e. aged T cells, homing molecule expression, antigen exposure) from intrinsic B cell defects. We hypothesized that life-history of cognate antigen exposure influences function and distribution of mucosal B cell populations during aging. These studies used immunoglobulin transgenic mice, whose cognate antigen nitrophenyl is not naturally encountered. Mice were periodically immunized orally from birth with T cell-dependent or -independent antigens. At various ages, intestines were analyzed for relative abundance, size, and cellular composition of Peyer’s Patches and isolated lymphoid follicles. Results revealed significantly more isolated lymphoid follicles in the distal region of aged mice when compared to young. Comparing immunized and control mice, flow cytometry data reveals a significant decrease in percentages of transgenic B cells in both tissues, and in animals receiving T cell independent antigen there were changes in CD4 and CD8 T cell distribution in aged mice. There was also a significant decrease of transgenic B cells in aged mice immunized with a T cell-dependent antigen for both Peyer’s Patches and isolated lymphoid follicles. Hence, preliminary data suggests significant role of cognate antigen exposure and further elucidates the mechanisms of age-related immune dysfunction.
Epithelial T cell gene expression is altered by obesity and Type 2 diabetes causing T cell exhaustion and barrier dysfunction (P3185)
Authors: Jameson Julie , Costanzo Anne , Clementsmith Zerlina , Cheung Kitty 
Published: January 2023

Abstract
Intraepithelial lymphocytes in tissues such as the skin and intestine play key roles in maintaining barrier integrity via the production of growth factors and cytokines. Obesity and type 2 diabetes induce defects in tissue repair and barrier function causing chronic nonhealing wounds and more severe cases of colitis. Our studies show that as obesity and type 2 diabetes progress, animals exhibit a dramatic decline in the number of epithelial T cells due to impaired T cell homeostatic proliferation. To understand how obesity impacts gene expression in the epithelium, we performed gene chip analysis and qPCR on cells isolated from the epithelium of obese mice. Our studies show that the normal gene expression program in both epithelial cells and intraepithelial T cells becomes disrupted. While T cells exhibit a gene profile indicative of exhaustion with a reduced ability to make growth factors and cytokines, the neighboring epithelial cells downregulate cell adhesion molecules and members of the IL-1 family such as IL-1F6. Returning the animals to a low fat diet does not rapidly restore the ability of T cells to recover their numbers and improve their function. However, blocking the low level of chronic inflammation that occurs with obesity improves T cell function in repair. These data indicate that controlling the myriad of epithelial complications associated with obesity will require turning down chronic inflammation and restoring the normal cellular program in intraepithelial T cells so immune responses at the critical barrier tissues are preserved.