bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of transplant rejection after the establishment of donor-specific tolerance
Authors: McIntosh Christine , Miller Michelle , Wang Ying , Chen Luqiu , Zhang Zheng Jenny , Wang Jiao-Jing , Allocco Jennifer , Chong Anita S F , Alegre Maria-Luisa 
Published: January 2023

Abstract
Patients weaned from immunosuppressive drugs can reject their graft after years of stability, often after an infection. We have modeled this in mice: infection with Listeria monocytogenes (Lm) at the maintenance phase of tolerance can precipitate rejection of a cardiac allograft. Here, we investigated which alloreactive Tconvs may mediate rejection after Lm infection. To track the function of allospecific Tconvs, we seeded tracer TCR75 cells, which recognize I-Ab-restricted donor Kd peptide, into B6 mice prior to Balb/c cardiac transplantation with or without tolerance induction by anti-CD154 + Balb/c splenocytes. ≥35 days post-transplantation, TCR75 cells persisting in tolerant mice developed a PD-1hi CD127lo exhausted-like phenotype and expressed the anergy markers FR4 and CD73. TCR75 cells were dysfunctional, exhibiting 10-fold less recall expansion compared to memory cells and lacked IFNγ and TNF production upon re-stimulation. Intriguingly, TCR75 cells in tolerant hosts remained dysfunctional after Lm infection, suggesting that they may not participate in infection-triggered rejection. Having found that programming T cell dysfunction in tolerance required persistence of the allograft for ~3 weeks, we tested whether T cells specific for alloantigens expressed transiently after transplantation, such as donor MHC Class II, remain functional during tolerance and may mediate rejection after Lm infection. We used tracer TEa cells specific for a donor Class II Eα peptide presented on I-Ab. During tolerance, TEa cells remained PD-1lo and CD73lo, and retained recall expansion and TNF production. We conclude that functional allospecific Tconvs present during tolerance may pose a previously unappreciated risk to the graft.
Marginal zone B cells induce T cell homeostatic proliferation following antibody-mediated lymphoablation
Authors: Hasgur Suheyla , Fan Ran , Valujskikh Anna 
Published: January 2023

Abstract
Antibody-mediated lymphoablation is commonly used in clinical transplantation. Using mouse model of heart transplantation and murine anti-thymocyte globulin (mATG) lymphoablation, we previously showed that B cell-derived IL-1β and IL-6 are critical mediators of homeostatic T cell proliferation. While marginal zone (MZ) B cells are best known as important sensors and amplifiers of inflammation, their role in depletion-induced lymphopenia has not been previously addressed. The goal of this study was to test the contribution of distinct B cell subsets to proinflammatory cytokine production and T cell homeostatic reconstitution. B6 (H-2b) recipients of BALB/c (H-2d) heart allografts were treated with mATG (d. 0, 4). At d. 8 posttransplant, the proportion of IL-1β, IL-6 and TNF-α secreting cells was significantly higher within MZ vs follicular (FO) B cell subset. Depletion of both FO and MZ B cells with anti-CD20 mAb in addition to mATG (d. -3, 11) significantly diminished T cell reconstitution and prolonged heart allograft survival compared to mATG treatment alone. Notably, specific MZ B cell depletion with anti-VLA4 and anti-LFA1α mAbs (d. -4, -2) resulted in similarly impaired T cells recovery along with improved heart allograft survival. Consistent with these findings, mATG treated Notch2flox/flox CD19Cre/+ mice, which lack MZ B cells but contain normal numbers of FO B cells, had delayed T cell recovery and prolonged heart allograft survival compared to WT recipients. These results show the critical role of MZ B cells in stimulating homeostatic T cell proliferation in lymphopenic heart allograft recipients and suggest that transient removal of MZ B cells may improve the efficacy of lymphoablative induction therapies.
The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity and promotes natural killer cell memory by regulating c-Myc and mitochondrial respiration
Authors: Dong Han , Adams Nicholas , Xu Yichi , Cao Jin , Chen Xi , Romee Rizwan , Sun Joseph Chai-Yuen , Glimcher Laurie H 
Published: January 2023

Abstract
Natural killer (NK) cells are critical mediators of host immunity to pathogens. Though historically being considered as a part of the innate immune system, NK cells exhibit adaptive features and can ‘remember’ stimuli like inflammation or viral infection and hence are capable of responding more robustly upon re-encountering the stimulation. Successful design of an NK cell-based therapy would ideally rely on harnessing NK cell memory, the key drivers and regulators of which remain poorly understood. Here, we demonstrate that the endoplasmic reticulum stress sensor IRE1α and its substrate transcription factor XBP1 drive NK cell responses against viral infection and tumors in vivo. IRE1α-XBP1 were essential for expansion of activated mouse and human NK cells and are situated downstream of the mTOR pathway. Transcriptome and chromatin immunoprecipitation analysis revealed c-Myc as a new and direct downstream target of XBP1 for regulation of NK cell proliferation. NK cells with c-Myc haploinsufficency phenocopied IRE1α deficiency, while c-Myc overexpression largely rescued the proliferation defect in IRE1α−/− NK cells. Like c-Myc, IRE1α also promotes oxidative phosphorylation in NK cells. Combined, our study identifies an IRE1α-XBP1-cMyc axis in NK cell immunity; and based on this work, we are currently investigating the role of IRE1 in NK cell memory using novel transgenic mouse models and small molecule drug treatment in primary human cells. We are also evaluating the therapeutic benefit of manipulating IRE1 function in CAR-NK cells to treat cancer. Our ongoing study should advance the current knowledge of NK cell memory and also open new opportunities in cancer therapy for patients with otherwise extremely poor prognoses.
cGAS-STING pathway mediates antitumor immunity of tumor cryoablation in syngeneic murine Rhabdomyosarcoma
Authors: Alshebremi Mohammad A , Myers Jay T , Kingsley Daniel , Huang Alex Yee-Chen 
Published: January 2023

Abstract
Tumor cryoablation, a medical procedure that utilizes ultra-cold temperatures to destroy in situ local tumor tissues, has been established for cure of many tumor types and for stimulation of the immune system. The mechanism of immune response to tumor cryoabltion are not well defined. To understand the molecular pathway of immune activation by cryoablation, we performed comprehensive analyses on the impact of tumor cryoablation on mononuclear phagocytic lineage cells and the antitumor immunity. Here, we show that cryoablation of a murine Rhabdomyosarcoma (RMS) tumor, an aggressive sarcoma affecting children and young adults, was able to induce the regression of tumor and the upregulation of the critical immune cytokines/chemokines profile and maturation markers of CD11c+ DCs. Moreover, cryoablation of RMS tumor initiates cGAS-STING signaling activation and type I interferon production in CD11c+ DCs, which are consequential in pro-inflammatory tumor microenvironment (TME). We also report that antitumor effects of cryoablation were more inhibitive, but not completely abrogated, in STING-deficient mice comparing with wild-type mice, indicating that both host-derived and tumor-intrinsic cGAS-STING signaling plays an important role in antitumor effects of tumor cryoablation. Taken together, our results demonstrate that tumor cryoablation induces antitumor immunity via cGAS-STING signaling in syngeneic Rhabdomyosarcoma (RMS) tumor, and this approach may help guide future immunotherapy to improve cancer treatment outcomes.
BRD4 inhibitors synergize with anti-PD1 in rescuing T cell exhaustion in acute myeloid leukemia by increasing TCF1 expressing CD8+ T cells
Authors: Romine Kyle Alexander , Cho Hyun-jun , Flynn Patrick , Kosaka Yoko , Byrd Kaelan , Lind Evan F 
Published: January 2023

Abstract
Acute myeloid leukemia (AML) is an aggressive myeloid lineage cancer with limited treatment options. Single-agent treatments with targeted inhibitors have resulted in some disease remissions, however, resistance almost always develops, prompting development of combinatorial treatment strategies. Studies have shown that AML patients exhibit markers of immune suppression such as increased levels of exhausted T cells (PD1/LAG3+) as well as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)1. Inhibitors targeting the BET family, which are histone readers, have been shown to increase IFNy and IL-2 production in T cells by inhibiting BATF—a known negative regulator of TCF1, as well as decrease PD-L12–4. We, therefore, hypothesized that combining BRD4i and anti-PD1 would synergize by modulating both tumor intrinsic biology (though MYC reduction) and boosting T cell activity. We have characterized a FLT3-ITD/TET2/Lys-Cre mouse model of AML and observed significantly increased numbers of PD1+/TIM3+/TCF1− T cells, Tregs, and MDSCs when compared to healthy mice. T cells derived from mice with AML have significantly reduced T cell proliferation upon co-stimulation with CD3 and CD28. Ex vivo treatment with BRD4i + aPD1 significantly increased T cell proliferation in AML mice and increased TCF1 expression in a dose dependent manner. In vivo treatment with BRD4i + aPD1 showed enhanced reduction of leukemic blasts, reduced PD-L1, and increased CD8+ T cell infiltration into the bone marrow. Our work highlights the efficacy of this novel drug combination in targeting tumor intrinsic and extrinsic factors in AML and identifies a potential novel role for BRD4 in regulating TCF1 expression in T cells.
Treg dysregulation contributes to pathogenesis of Myelodysplastic syndrome
Authors: Camacho Virginia , Matkins Victoria , Patel Sweta , Anderson Ashlyn , Landuy Ashley E , Ferrell Paul Brent , Maynard Craig L , Harrington Laurie E , Turnquist Heth Roderick , Welner Robert S 
Published: January 2023

Abstract
A strong clinical correlation exists between a history of autoimmunity and Myelodysplastic syndromes (MDS), but immune etiology remains unclear. However, a hallmark of disease is that Regulatory T cells (Tregs) are significantly altered in MDS patients. Thus, Tregs can be used as prognostic indicators of severity. Additionally, dysregulated CD4 T cell responses are causally linked to inflammatory disorders in MDS patients, yet the cellular dynamics that underlie these responses is poorly understood. We now show that Treg dysfunction mimics the pre-leukemic phenotypes of MDS including increased HSC proliferation and myeloid-skewed differentiation. Furthermore, we show that mice with Treg-restricted MDS driver mutations, TET2 and ASXL1, develop an inflammatory disease with unstable Tregs that secrete inflammatory cytokines and lose immunosuppressive capacities. TET2 and ASXL1 deficiency in Tregs leads to hyperproliferation of CD4+Foxp3+ T cells with a conversion into IL-17-producing cells. Importantly, CD4 and CD8 T cells are also altered in MDS and show impaired effector function as well as hallmarks of T cell exhaustion and anergy leading to expansion of malignant clones. Together, this indicates that T cell abnormalities and lack of immune function effectively propel leukemic evolution. Our findings indicate that the pro-inflammatory environments of MDS deteriorate T cell stability and accelerate the expansion of hematopoietic stem/progenitor cells carrying MDS-associated pre-leukemic mutations. Therapeutic intervention targeting both Tregs and effector cells in pre-malignant diseases such as MDS are likely to prevent progression to less treatable acute myeloid leukemia.
Arginase-1 production by myeloid cells in tumor microenvironment induce inflammasome activation and activate PI3K pathway in tumor-associated macrophages in head and neck cancer
Authors: Momen-Heravi Fatemeh , Dubey Sunil K 
Published: January 2023

Abstract
Tumor-associated macrophages (TAMs) express cytokines and mediators that can suppress T cell recruitment and activation in the tumor microenvironment, support tumor growth, and promote resistance to therapy. We found that Arginase-1 is produced in high quantities by TAMs and tumor cells in head and neck cancer tumors with different background mutations. High levels of Arginase-1 were found in tumor samples and the circulation of patients and animal models of head and neck cancer.
Arginase-1 is released into the cellular microenvironment and packed into the exosomes in a metabolically active form. Mechanistically, Arginase-1 further propagated the anti-inflammatory macrophage phenotype in the tumor microenvironment and induced the epithelial-mesenchymal transition (EMT) by activation of STAT3 and beta-catenin. Arginase-1 released from the tumor further induced activation of the autophagy cascade and the PI3K pathway in TAMs. Mechanistic results showed that STAT3 activation by Arginase-1 containing exosomes has a positive feedback effect on the expression of Arginase-1, Il-1β, and lead to inflammasome activation. The silencing of STAT3 negated the effect of Arginase-1 containing exosomes and led to modulation of the inflammasome activation in the head and neck cancer tumor microenvironment. These results indicate a mechanistic role of TAMs and Arginase-1 containing exosomes in the tumor microenvironment by activation of autophagy and inflammasome, and induction of the EMT. The mechanistic links presented in this study regarding the role of arginase in head and neck cancer pathogenesis could be targeted as therapeutic strategies.
cDC1 prime and receive help from CD4 T cells to promote anti-tumor responses
Authors: Ferris Stephen T , Wu Renee , Durai Vivek , Murphy Theresa L , Murphy Kenneth M 
Published: January 2023

Abstract
CD4 T cells are thought to help promote anti-tumour responses by ‘licensing’ antigen presenting cells (APCs) that activate CD8 T cells. Conventional type 1 dendritic cells (cDC1s) are responsible for cross-presentation of tumour-derived antigens to CD8 T cells. Prevailing models presume that the cDC1 is licensed by CD4 T cells that are themselves activated by a distinct cDC subset, the cDC2. The recent finding that neoantigens presented by major histocompatibility complex (MHC) class II molecules can promote rejection of tumours that lack MHC class II (MHC-II) surface expression is consistent with an indirect action of CD4 T cells, such as cDC1 licensing. However, no study has directly identified the APC that primes the CD4 T cells responsible for licensing or clearly identified the target of CD4 licensing in vivo. Here, we generated cDC1-specific Cre expressing mouse strain to inactivate or induce expression of MHC-I, MHC-II, or CD40 specifically within the cDC1 lineage. Using a tumour model that relies on CD8 T cells and CD4 T cells for rejection, we discovered that priming of CD4 T cells against tumour-derived antigens, in contrast to soluble antigens, relied overwhelmingly on the cDC1 and not the cDC2. cDC1 do not simply transport antigen to lymph nodes for processing by cDC2, since lack of MHC-II expression on cDC1 prevented CD4 T cell priming. We also found that CD40 signaling not only affects licensing of cDC1 for CD8 T cell priming, but is also critical for the activation of CD4 T cells. Thus, in the setting of tumour-derived antigens, cDC1 function as an autonomous platform capable of priming both CD4 and CD8 T cells and orchestrating their cross-talk required for optimal anti-tumour immunity.
Granuloma in tumor-draining lymph nodes impairs tumor-reactive CD8+ T cell trafficking in immune-checkpoint therapy
Authors: Cho Eunjung , Han Chungyong , Kim Seon-Hee , Choi Beom K. 
Published: January 2023

Abstract
Based on the unique properties of 4-1BB (CD137) signaling – strong enhancer of CD8+ T cell proliferation, agonistic anti-4-1BB mAbs are under evaluation as cancer therapeutics in the clinic. However, there are concerns about adverse effects in using 4-1BB agonist. Here we found that hyper-activation of 4-1BB signals induced the accumulation of IFN-γ-producing PD-1+CD8+ T cells in secondary lymphoid organs of tumor-bearing mice by increasing the numbers of each dividing CD8+ T cells, and which were beneficial in suppressing tumor growth in the early phase of anti-4-1BB triggering. However, when the tumor-bearing mice were repeatedly exposed to anti-4-1BB mAb, the mice developed granuloma in tumor draining lymph nodes (TDLNs) by recruiting and accumulating macrophages via CD8+ T cell-IFN-γ axis, which accompanied the excessive LN swelling and eventually the impaired proliferation and trafficking of CD8+ T cells in TDLNs. Our data not only reveals the granuloma in TDLN as unexpected adverse effects of anti-4-1BB mAb, but also provides an insight that the granuloma in TDLN is the other side of the enhanced CD8+ T cell responses.
NF-kB1 induces T cell dysfunction to promote colon tumorigenesis
Authors: Lu Chunwan , Klement John D. , Xiao Wei , Ibrahim Mohammed L. , Smith Alyssa D. , Yang Dafeng , Browning Daren , Munn David H. , Liu Kebin 
Published: January 2023

Abstract

Background and aims
Chronic colonic inflammation drives colon tumorigenesis. Chronic infection-associated inflammation causes T cell exhaustion/dysfunction. NF-kB is a molecular link between colonic inflammation and colorectal cancer. We aimed at testing the hypothesis that the p50 NF-kB (NF-kB1) regulates T cell dysfunction to promote colon tumor immune evasion and development.

Methods
Nfkb1 knock out (p50 KO), Nfkb1 KO chimera mice, Nfkb1 KO colon tumor cells were used to determine p50 NF-kB function in colon tumor development. RNA-Seq, chromatin immunoprecipitation, and electrophoresis mobility shift assay were used to elucidate molecular mechanism of NF-kB1 action. Flow cytometry was used to analyze cytotoxic T lymphocytes.

Results
p50 KO mice showed a significantly decrease in tumorigenesis. However, mice with p50 deficiency only in immune cells also exhibited a significant decrease in tumorigenesis, and p50-sufficient colon tumor cells also grew significantly slower in p50 KO mice than in WT mice. RNA-Seq identified Gzmb as a p50 NF-kB target gene. p50 KO mice have significantly higher tumor-infiltrating granzyme B+ CTLs than WT mice, and CTL granzyme B protein level is also significantly higher in p50 KO mice than in WT mice. A kB sequence element was identified at the Gzmb promoter and p50 NF-kB directly binds to this kB element in T cells to repress Gzmb expression.

Conclusion
NF-kB1 has opposing functions in tumor cells and T cells in vivo. The p50 NF-kB represses Gzmb expression to confer colon tumor-infiltrating CTL a dysfunctional phenotype to promote colon tumor immune evasion, resulting in enhanced colon tumorigenesis and growth.
PD1 and LAG3 converge to limit polyfunctionality and systemic immunity
Authors: Andrews Lawrence Peter , Manne Sasikanth , Wherry E. John , Workman Creg , Vignali Dario 
Published: January 2023

Abstract
Targeting PD1 has yielded clinical success across many tumor types, yet a significant proportion of patients remain unresponsive to treatment. Co-expression of PD1 and LAG3 inhibitory receptors (IRs) on CD8+ tumor-infiltrating T cells (TIL) is associated with an exhausted phenotype and dual blockade synergistically limits tumor growth, greater than targeting PD1 alone.
The cellular and mechanistic basis for PD1/LAG3 synergy is unknown. We have generated conditional knockin mice that facilitates the CD8+ T cell-restricted deletion of Pdcd1 and/or Lag3 when crossed to E8ICre.GFP. These mice have also been crossed with a pMEL TCR transgenic mouse, congenically marked to allow intrinsic analysis of PD1 and/or LAG3-deficient CD8+ T cells, and controls, in a ‘quad’ co-adoptive transfer system.
Pdcd1L/L and/or Lag3L/L-yfp E8ICre.GFP mice show reduced B16-F10 tumor growth with improved survival, compared to Lag3L/L-yfp E8ICre.GFP mice and controls. CD8+ TIL frequency is increased with loss of both IRs, as a result of enhanced proliferation. Although expression of TIM3, TIGIT and 2B4 IRs is maintained, CD8+ TIL isolated from Pdcd1L/LE8ICre.GFP and Pdcd1L/ Lag3L/L-yfp E8ICre.GFP mice show increased polyfunctionality, by IFNg, TNFa and GzmB release. This was confirmed to be largely driven by effector and chemoattractive secretions by analysis with a 28-plex single-cell cytokine response panel (Isoplexis).
Overall, these data suggest that PD1 and LAG3 synergize to have a dominant effect on CD8+ TIL and limit antitumor immune effects, as intrinsic removal of both IRs results in reduced tumor growth that substantially impacts anti-tumor immunity. These results are encouraging for the development of co-targeting LAG3 and PD1 in the clinic.
Evaluation of immune checkpoints in small cell lung cancer: implications for immunotherapy
Authors: Thomas Portia , Maddox Sarah , Iams Wade , Quaranta Vito , Tyson Darren , Lovly Christine 
Published: January 2023

Abstract

Introduction
The FDA recently approved Atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor, for first-line combinatory treatment in patients with extensive-stage small cell lung cancer. Across several cancer types, immunotherapy has been shown to provide durable benefit in patients with metastatic disease. However, Atezolizumab only improves overall survival by 2 months. This could be due to the fact that &lt;20% of patients express &gt;1% tumor PD-L1 positivity. We assert that a better understanding of this immune contexture – defined as abundance and type of checkpoint molecules in SCLC – may provide important criteria for patient stratification.

Objectives
In these studies, we will test the hypothesis that immune checkpoints in addition to the PD-1/PD-L1 axis play a role in immune evasion in SCLC.

Methods
To evaluate expression of immune checkpoint molecules, we acquired bulk RNA-Seq data of SCLC cell lines and primary tumor specimens. Further, we generated tissue-microarrays containing &gt;20 unique cell lines and &gt;200 unique patient specimens with fully annotated clinical data to confirm expression of these molecules by immunohistochemistry.

Results
Preliminary RNA-Seq analyses show low PD-L1 expression in SCLC cell lines and primary tumors. Further, ubiquitously high expression of certain checkpoint molecules (B7-H3) is seen. Future analysis will confirm abundance and type of checkpoint molecules as well as capture interpatient heterogeneity.

Conclusions
Understanding the checkpoint molecules present in SCLC could further understanding of SCLC immune suppression, ultimately leading to optimal single-agent immunotherapy deployment and rational, effective combination therapy for patients with SCLC.