Abstract While T-cell engager (TCE) therapies have demonstrated clear clinical benefit, their broader application remains limited by the restricted repertoire of tumor-specific surface antigens. Targeting HLA-restricted peptides (pHLA) derived from intracellular tumor antigens offers an opportunity to expand the reach of TCEs to solid tumors. Telomerase reverse transcriptase (TERT) represents such an intracellular target, as it is highly expressed in approximately 85-95% of human tumors. We have previously described CBX-663, a potent and specific TCR-mimetic (TCRm) TCE targeting the TERT540/HLA-A*02:01 complex, and its activity in hematologic cancer models. Here, we characterize its therapeutic potential in preclinical solid tumor models. CBX-663 consists of a single humanized CD3-binding domain and two fully human TCRm domains that recognize TERT540/HLA-A*02:01 in a bivalent format. CBX-663 binds TERT540 pHLA with sub-nM affinity and low-pM avidity, leading to potent T-cell-mediated cytotoxicity across multiple TERT- and HLA-A*02:01-positive solid tumor cell lines. Subsequent analysis revealed that responsive cell lines exhibit higher HLA-A*02:01 expression than non-responders. Notably, some of the highest responding cell lines carry TERT promoter mutations, which are well known to elevate TERT transcription and may increase pHLA presentation. CBX-663 achieved robust tumor control in a disseminated NSCLC COR-L23-A2 model using PBMC-humanized NSG mice and induced tumor growth delay in a subcutaneous NSCLC NCI-H1703 model established in humanized CD34+ (huCD34) mice. Additional efficacy studies are ongoing. To further characterize specificity, X-scan analysis of TERT540 peptide was conducted and revealed multiple residues critical for CBX-663 recognition of TERT540 pHLA. A screen of >6,000 human membrane proteins identified no detectable off-target interactions of CBX-663. In addition, no activity was observed against TERT- or HLA-A*02:01-negative cells, unrelated HLA alleles, or normal HLA-A*02:01-positive primary cells from diverse tissues. CBX-663 induced moderate cytokine release upon treatment of HLA-A*02:01-positive PBMCs in the absence of tumor cells, consistent with previously reported targeting of monocytes and B cells by TERT-directed T cell therapies in preclinical models. Cytokine induction with CBX-663 was markedly lower than that elicited by a CD123-targeting TCE tested under identical conditions. Importantly, repeat dosing of CBX-663 was well tolerated in non-tumor-bearing huCD34 mice reconstituted with human hematopoietic cells, with minimal cytokine release and transient changes in leukocyte populations. Collectively, these data support the therapeutic potential of CBX-663 in solid tumors. IND-enabling studies are currently underway. Citation Format: Yu Huang, Ricard Masia, Bhupal Ban, Qunyan Yu, Jennifer Helble, Jessica Jimenez, Delainey O’Connor, Preethi Sankaran, Christine A. Devlin, Melissa Bikowitz, Emily McNally, Sarah Jaffe, Tanzila Rahman, Alona Kulesha, Andrew Wolpert, Shawn O’Malley, Yue Li, Michael Jennings, Galina Gabriely, Mathilde A. Poussin, Daniel J. Powell, Nga Sze Amanda Mak, Tao Wang, Geraldine L. Paulus, Michi Schebesta, Benjamin Lee, Dmitri Wiederschain. CBX-663, a first-in-class TCR-mimetic T-Cell Engager targeting the TERT peptide-HLA complex, mediates potent cytotoxicity in vitro and tumor inhibition in vivo in preclinical models of solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1635.

IFN-β, a type I interferon, has been used as a first-line therapy for patients with multiple sclerosis (MS) for more than 30 years; however, the cellular and molecular basis of its therapeutic efficacy remains unclear. Here, we first used experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, to show that the therapeutic effects of IFN-β were associated with a down-regulation of microRNA-21 (miR-21) and pathogenic TH17 (pTH17) cells. In vitro experiments demonstrated that genetic knockout of miR-21 directly inhibited pathogenic TH17 cell differentiation. Further mechanistic investigations revealed that miR-21 promoted pathogenic TH17 differentiation by inhibiting the transcription factor Forkhead box protein O1 (Foxo1). Accordingly, miR-21 loss abrogated pathogenic TH17 differentiation and conferred resistance to EAE. Treatment of T cell monocultures with IFN-β showed that IFN-β did not directly limit miR-21 expression. Instead, IFN-β treatment inhibited the secretion of miR-21-inducing cytokines from myeloid cells, reduced miR-21 induction within cocultured T cells, and inhibited pathogenic TH17 development. In patient samples, immunophenotypic and targeted transcriptomic analyses revealed that compared with IFN-β treatment responders, nonresponders expressed elevated miR-21-inducing cytokines within myeloid cells, alongside increased miR-21 and pathogenic TH17 cytokines within CD4+ T cells. Direct miR-21 inhibition reduced pathogenic TH17 differentiation in nonresponder CD4+ T cells. These results suggest that type I IFN signaling limits central nervous system autoimmunity by inhibiting miR-21-mediated pathogenic TH17 development. miR-21 inhibition may be of potential therapeutic value specifically for the IFN-β nonresponder cohort.

Telomerase Reverse Transcriptase (TERT) is an oncogenic driver highly expressed in ~90% of all tumors, including hematologic malignancies such as acute myelogenous leukemia (AML). However, therapeutic targeting of TERT has remained challenging. The presentation of HLA-A*02:01-restricted TERT540 peptide by tumor cells represents an opportunity to target TERT-expressing malignancies using TCR-mimetic (TCRm) antibodies that recognize peptide-Human Leukocyte Antigen (pHLA) complexes. The feasibility of this strategy is supported by previous studies demonstrating that TERT-specific cytotoxic lymphocytes (CTLs) can target and kill leukemia cell lines in vitro as well as in mouse xenograft models in vivo. Using our T-Bolt® platform, we have developed CBX-663, a potent and specific TCRm-based T cell engager (TCE) that targets the TERT540 / HLA-A*02:01 pHLA complex on the surface of tumor cells through bivalent interaction, while simultaneously engaging CD3 on T cells. CBX-663 binds to TERT540 pHLA with sub-nM affinity and low-pM avidity, inducing potent, target-dependentT-cell activation and T-cell-mediated cytotoxicity across multiple TERT- and HLA-A*02:01-positive leukemia cell lines in vitro, with EC50 values ranging from 4.4 to 30.9 pM. Furthermore, CBX-663 shows potent cytotoxicity against primary AML blasts ex vivo, at clinically relevant effector-to-target (E:T) ratios (~1:20 and lower). Notably, CBX-663 demonstrates activity against primary AML blasts with a complex karyotype and TP53 mutation, highlighting the promise of targeting TERT in AML patient subpopulations with poor prognosis. Furthermore, leukemic stem cells (LSC), defined as CD45low CD33- CD34+ CD38-, are even more potently targeted by CBX-663 ex vivo, consistent with known high levels of telomerase activity in these cells. Effective targeting of LSC is highly desirable given their role in initiating and maintaining malignant proliferation. In vivo, treatment with CBX-663 leads to tumor growth control in a Cell-Derived Xenograft (CDX) AML model in PBMC-humanized mice. To assess its safety profile, CBX-663 was evaluated in multiple studies. On-target activity of CBX-663 against CD34+ bone marrow progenitor cells was studied in an in vitro colony-forming unit (CFU) assay. Consistent with known transient expression of TERT in this cell population, CBX-663 treatment resulted in a dose-dependent decrease in colony counts, but to a lesser extent than a CD123-targeting TCE which was included as a comparator. Comparison of EC50 values achieved with CBX-663 in cytotoxicity assays against AML cell lines versus normal progenitors in the CFU assay suggests the presence of an acceptable therapeutic index. To further investigate the impact of CBX-663 on human bone marrow progenitors and peripheral blood cells, repeated administration of CBX-663 (at dose levels demonstrated to be efficacious in vivo) was performed in non-tumor-bearing humanized CD34 (huCD34) mice which contain all human hematopoietic lineages. The treatment was well tolerated, with no deleterious effects on body weight or general health over vehicle control. An initial decrease in white blood cells and several immune cell subsets was observed in peripheral blood, but this phenomenon was reversible, with the exception of a moderate decrease in neutrophils that persisted during the period of study observation (2 weeks after the last dose). Red blood cells and platelets were minimally affected, indicating an overall manageable bone marrow toxicity profile. To further study its safety profile, CBX-663 was tested in vitro in a panel of 27 primary human cell types from multiple HLA-A*02:01-positive vital organs and tissues. Co-culturing primary human cells with PBMCs and CBX-663 did not induce T cell activation, even at concentrations far exceeding efficacious doses in vitro. Additional studies confirmed the specificity and developability of CBX-663, including a pharmacokinetic (PK) study in humanized FcRn mice, which demonstrated a conventional IgG-like PK profile with a half-life ≥12 days.Collectively, these data strongly support the therapeutic potential of CBX-663 in myeloid malignancies, including AML. IND enabling studies are currently underway with the goal of advancing CBX-663 into clinical development.

Traumatic brain injury (TBI) remains a leading cause of chronic neurological impairment, yet the cellular mechanisms underlying long-term neurodegeneration in TBI remain incompletely understood. Astrocytes, the most abundant glial cell type, are central to maintaining neuroglial and neurovascular homeostasis. Following TBI, however, astrocytic activation contributes to sustained inflammation and neurotoxicity. In this study, we employed immunohistochemistry and RNA sequencing to longitudinally profile astrocyte morphology and transcriptional states at acute (2 days), subacute (2 weeks), and chronic (1 year) stages after controlled cortical impact in mice. We identified a temporally evolving astrocyte response—beginning with a pro-inflammatory profile acutely, transitioning through a profile suggestive of mixed inflammatory and neurodegenerative signatures subacutely, and culminating in a chronic state marked generally by expression of Alzheimer’s and Parkinson’s disease-associated genes. Notably, a subset of astrocyte-derived progenitor cells also was found up to one-year post-injury, expressing markers associated with neurogenesis. These findings reveal that astrocyte activation is not transient but persists chronically, undergoing a dynamic shift from inflammation to degeneration. The observed parallels between astrocyte states in chronic TBI and neurodegenerative disorders underscore their potential role in post-traumatic cognitive decline and highlight astrocyte-targeted interventions as a promising avenue for therapeutic development. Transcriptomic analysis of astrocytes in the acute, subacute, and chronic phases after traumatic brain injury reveal an evolving dynamic shift from neuroinflammation to neurodegeneration, and to a limited extent, regeneration.

Abstract While T-cell engaging therapies have demonstrated clear clinical benefit in the treatment of B-cell malignancies, their application to myeloid malignancies remains a challenge due to the limited repertoire of suitable tumor specific surface antigens. Targeting HLA-restricted peptides (pHLA) derived from intracellular cancer antigens provides an opportunity to explore the entire cancer proteome. CG1 (FLLPTGAEA) has been validated as an HLA-A*02:01 restricted leader peptide from Cathepsin G (CTSG) and is abundantly presented by leukemic versus normal myeloid cells. TCR-mimetic (TCRm) antibodies are ideally suited to target pHLA with high potency and specificity and can be engineered and manufactured using standard antibody technologies. Here we report the preclinical characterization of CBX-250, a novel CG1/HLA-A2 TCRm-CD3 bispecific T-Cell Engager (TCE). CBX-250 induced potent T-cell activation and T-cell mediated killing of leukemia cell lines with varying levels of target antigen density with sub-nM EC50 in vitro. In vivo, a closely related precursor of CBX-250 demonstrated potent tumor control in various AML and CML CDX models at doses as low as 0.01mpk. Although CTSG is a serine protease stored in neutrophil azurophilic granules, the CG1 peptide is preferentially presented by leukemia cells, as validated by mass spectrometry. Moreover, when co-culturing PBMCs with HLA-A2 neutrophils, we did not observe any CBX-250-mediated T-cell activation or IFNγ production. In silico predictions identified HLA-A2-restricted human peptides that share sequence or structural similarity to CG1. We determined the cross-reactivity risk of CBX-250 to be low, based on T-cell activation and T-cell mediated cytotoxicity assays against cells pulsed with supra-physiological concentrations of these peptides. Moreover, we observed no activity against target-negative cancer cells, including a CTSG-KO cell line. To further assess the specificity of CBX-250, we screened a panel of normal cells and found no meaningful T-cell activation or IFNγ production at CBX-250 concentrations exceeding its EC90. Finally, the CBX-250 precursor molecule demonstrated favorable safety in a double transgenic mouse model expressing human HLA-A2 and CG1. Following sequence optimization, CBX-250 demonstrated robust serum and pH stress stability and a favorable melting temperature, while retaining excellent potency and specificity. A full suite of analytical and biophysical assessments supports CBX-250’s favorable developability profile. In summary, these data provide strong preclinical evidence of the potency, specificity, safety, and developability of CBX-250, a novel, first-in-class, off-the-shelf, TCRm-based TCE for the treatment of myeloid malignancies. Citation Format: Geraldine Paulus, Benjamin Lee, Preethi Sankaran, Tanzila Rahman, Jessica Jimenez, Delainey O'Connor, Simon Yue, Yu Huang, Melissa Bikowitz, Sarah Jaffe, Shawn O'Malley, Bhupal Ban, Galina Gabriely, Tao Wang, Amanda Mak, Michael Princiotta, Chunhua Shi, Helen He, Ningping Feng, Jun Yan, Timothy Heffernan, Gheath Alatrash, Jeffrey Molldrem, Dmitri Wiederschain. Characterization of CBX-250, a first-in-class TCR-mimetic-based T-cell engager targeting a cathepsin G peptide-HLA complex for the treatment of myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1236.

Dietary proteins are taken up by intestinal dendritic cells (DCs), cleaved into peptides, loaded to major histocompatibility complexes, and presented to T cells to generate an immune response. Amino acid (AA)-diets do not have the same effects because AAs cannot bind to major histocompatibility complex to activate T cells. Here, we show that impairment in regulatory T cell generation and loss of tolerance in mice fed a diet lacking whole protein is associated with major transcriptional changes in intestinal DCs including downregulation of genes related to DC maturation, activation and decreased gene expression of immune checkpoint molecules. Moreover, the AA-diet had a profound effect on microbiome composition, including an increase in Akkermansia muciniphilia and Oscillibacter and a decrease in Lactococcus lactis and Bifidobacterium. Although microbiome transfer experiments showed that AA-driven microbiome modulates intestinal DC gene expression, most of the unique transcriptional change in DC was linked to the absence of whole protein in the diet. Our findings highlight the importance of dietary proteins for intestinal DC function and mucosal tolerance.

Abstract MicroRNA (miRNA) expression profiling studies revealed a number of miRNAs dysregulated in the malignant brain tumor glioblastoma. Molecular functions of these miRNAs in gliomagenesis are mainly unknown. We show that inhibition of miR-10b, a miRNA not expressed in human brain and strongly upregulated in both low-grade and high-grade gliomas, reduces glioma cell growth by cell-cycle arrest and apoptosis. These cellular responses are mediated by augmented expression of the direct targets of miR-10b, including BCL2L11/Bim, TFAP2C/AP-2γ, CDKN1A/p21, and CDKN2A/p16, which normally protect cells from uncontrolled growth. Analysis of The Cancer Genome Atlas expression data set reveals a strong positive correlation between numerous genes sustaining cellular growth and miR-10b levels in human glioblastomas, while proapoptotic genes anticorrelate with the expression of miR-10b. Furthermore, survival of glioblastoma patients expressing high levels of miR-10 family members is significantly reduced in comparison to patients with low miR-10 levels, indicating that miR-10 may contribute to glioma growth in vivo. Finally, inhibition of miR-10b in a mouse model of human glioma results in significant reduction of tumor growth. Altogether, our experiments validate an important role of miR-10b in gliomagenesis, reveal a novel mechanism of miR-10b–mediated regulation, and suggest the possibility of its future use as a therapeutic target in gliomas. Cancer Res; 71(10); 3563–72. ©2011 AACR.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality. The innate and adaptive immune responses play an important role in the pathogenesis of TBI. Gamma-delta (γδ) T cells have been shown to affect brain immunopathology in multiple different conditions, however, their role in acute and chronic TBI is largely unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year following injury in a mouse model. TCRδ-/- mice are characterized by reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We find that the Vγ1 and Vγ4 γδ T cell subsets play opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation. Vγ1 γδ T cells, however, secrete TGF-β that maintains microglial homeostasis and dampens TBI upon infiltrating the brain. These findings provide new insights on the role of different γδ T cell subsets after brain injury and lay down the principles for the development of targeted γδ T-cell-based therapy for TBI.

Supplementary Methods, Figures 1-10, Table 1 from Human Glioma Growth Is Controlled by MicroRNA-10b

A disequilibrium between immunosuppressive Tregs and inflammatory IL-17–producing Th17 cells is a hallmark of autoimmune diseases, including multiple sclerosis (MS). However, the molecular mechanisms underlying the Treg and Th17 imbalance in CNS autoimmunity remain largely unclear. Identifying the factors that drive this imbalance is of high clinical interest. Here, we report a major disease-promoting role for microRNA-92a (miR-92a) in CNS autoimmunity. miR-92a was elevated in experimental autoimmune encephalomyelitis (EAE), and its loss attenuated EAE. Mechanistically, miR-92a mediated EAE susceptibility in a T cell–intrinsic manner by restricting Treg induction and suppressive capacity, while supporting Th17 responses, by directly repressing the transcription factor Foxo1. Although miR-92a did not directly alter Th1 differentiation, it appeared to indirectly promote Th1 cells by inhibiting Treg responses. Correspondingly, miR-92a inhibitor therapy ameliorated EAE by concomitantly boosting Treg responses and dampening inflammatory T cell responses. Analogous to our findings in mice, miR-92a was elevated in CD4+ T cells from patients with MS, and miR-92a silencing in patients’ T cells promoted Treg development but limited Th17 differentiation. Together, our results demonstrate that miR-92a drives CNS autoimmunity by sustaining the Treg/Th17 imbalance and implicate miR-92a as a potential therapeutic target for MS.

Abstract Traumatic brain injury (TBI) results in both morbidity and mortality in which both innate and adaptive immune responses play an important role in the pathogenesis of TBI. Nonetheless, the role of gamma-delta (γδ) T cells in acute and chronic TBI is unknown. Here, we show that γδ T cells affect the pathophysiology of TBI as early as one day and up to one year after injury. TCRδ−/− mice exhibited reduced inflammation in acute TBI and improved neurocognitive functions in chronic TBI. We found that Vγ1 and Vγ4 γδ T cell subsets played opposing roles in TBI. Vγ4 γδ T cells infiltrate the brain and secrete IFN-γ and IL-17 that activate microglia and induce neuroinflammation, whereas Vγ1 γδ T cells infiltrate the brain and secrete TGF-β that maintains microglial homeostasis and dampens TBI. These findings provide new insights on the role of different γδ T cell subsets after brain injury and provide novel avenues for the development of targeted γδ T-cell-based therapy for the treatment of TBI.

Myeloid suppressor cells promote tumor growth by a variety of mechanisms which are not fully characterized. We identified myeloid cells (MCs) expressing the latency-associated peptide (LAP) of TGF-beta on their surface and LAP(Hi) MCs that stimulate Foxp3(+) Tregs while inhibiting effector T cell proliferation and function. Blocking TGF-beta inhibits the tolerogenic ability of LAP(Hi) MCs. Furthermore, adoptive transfer of LAP(Hi) MCs promotes Treg accumulation and tumor growth in vivo. Conversely, anti-LAP antibody, which reduces LAP(Hi) MCs, slows cancer progression.. Single-cell RNA-Seq analysis on tumor-derived immune cells reveal LAP(Hi) dominated cell subsets v ! -h distinct immunosuppressive signatures, including those with high levels of MHCII and PD-L1 genes. Analogous to mice, LAP is expressed on myeloid suppressor cells in humans, and these cells are increased in glioma patients. Thus, our results identify a previously unknown function by which LAP(Hi) MCs promote tumor growth and offer therapeutic intervention to target these cells in cancer.

Interleukin-17 (IL-17) is a major inflammatory cytokine implicated in colorectal cancer (CRC) development. However, the mechanisms that control tumorigenic IL-17 signaling are poorly understood. Recently, expression changes and polymorphisms in the small non-coding RNA, microRNA-146a (miR-146a), have been associated with clinical outcomes in inflammatory bowel disease and CRC patients. Here, we identified a novel role for miR-146a as a major negative regulator of colonic inflammation and tumorigenesis via modulation of IL-17 responses. MiR-146a-deficient mice are susceptible to both colitis-associated and sporadic CRC, and present with enhanced tumorigenic IL-17 signaling. Within myeloid cells, miR-146a targets RIPK2, an intermediate in NOD2 signaling, to limit myeloid cell-derived IL-17-inducing cytokines and restrict colonic IL-17 levels. Accordingly, myeloid cell-specific deletion of miR-146a leads to CRC susceptibility. Moreover, within intestinal epithelial cells (IECs), miR-146a targets TRAF6, an intermediate in IL-17R signaling, to restrict IEC responsiveness to IL-17. MiR-146a within IECs further suppresses CRC by targeting PTGES2, an enzyme for PGE2 synthesis. IEC-specific deletion of miR-146a confers marked CRC susceptibility. Importantly, preclinical administration of miR-146a mimic or direct inhibition of miR-146a targets, TRAF6/RIPK2 can ameliorate CRC. In conclusion, miR-146a prevents CRC by two interlinked mechanisms: 1) by limiting myeloid cell-mediated IL-17 production; and 2) by inhibiting tumorigenic IL-17R signaling in IECs. Overexpression of miR-146a may be a promising therapeutic approach for CRC to limit multiple pathways converging on tumorigenic IL-17 signaling.

Chronic inflammation can drive tumor development. Here, we have identified microRNA-146a (miR-146a) as a major negative regulator of colonic inflammation and associated tumorigenesis by modulating IL-17 responses. MiR-146a-deficient mice are susceptible to both colitis-associated and sporadic colorectal cancer (CRC), presenting with enhanced tumorigenic IL-17 signaling. Within myeloid cells, miR-146a targets RIPK2, a NOD2 signaling intermediate, to limit myeloid cell-derived IL-17-inducing cytokines and restrict colonic IL-17. Accordingly, myeloid-specific miR-146a deletion promotes CRC. Moreover, within intestinal epithelial cells (IECs), miR-146a targets TRAF6, an IL-17R signaling intermediate, to restrict IEC responsiveness to IL-17. MiR-146a within IECs further suppresses CRC by targeting PTGES2, a PGE2 synthesis enzyme. IEC-specific miR-146a deletion therefore promotes CRC. Importantly, preclinical administration of miR-146a mimic, or small molecule inhibition of the miR-146a targets, TRAF6 and RIPK2, ameliorates colonic inflammation and CRC. MiR-146a overexpression or miR-146a target inhibition represent therapeutic approaches that limit pathways converging on tumorigenic IL-17 signaling in CRC.

The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1 + DC in the duodenal LP and XCR1 + DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1 + and XCR1 + DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1 + and XCR1 + DC as region-specific physiologic regulators of intestinal homeostasis.

Glioblastoma (GBM) is an aggressive and incurable brain tumor; its malignancy has been associated with the activity of tumor infiltrating myeloid cells. Myeloid cells play important roles in the tumor control by the immune response, but also in tumor progression. Indeed, GBM exploits multiple mechanisms to recruit and modulate myeloid cells. The Aryl Hydrocarbon Receptor (AHR) is a ligand activated transcription factor implicated in the regulation of myeloid cells. In this review, we will summarize current knowledge on the AHR role in the control of myeloid cells and its impact on GBM pathogenesis.

Immunotherapy that acts by counteracting the suppressive environment established by the tumor became a very promising approach for the treatment of cancer. Regulatory immune cells promote cancer by suppressing antitumor immune responses, but there are few cell surface molecules that can specifically be targeted to neutralize their function. We characterized a regulatory T-cell population that expresses surface latency-associated peptide (LAP). LAP is an adaptor and regulator of TGF-beta, a potent immunosuppressive cytokine. An increase in LAP+ CD4 T cells has been reported in human cancer, including head and neck and colorectal cancer. To study the regulatory role of LAP+ cells in cancer, we developed a murine monoclonal anti-LAP antibody. We found that treatment with anti-LAP antibody reduces tumor growth and increases survival in various cancer models, including colon carcinoma, glioblastoma and melanoma. Anti-LAP antibody is able to block TGF-beta release from cells expressing LAP and also reduces both the number and suppressive abilities of tumor-associated LAP+ regulatory cells. Anti-LAP antibody treatment triggers a profound peripheral immune response by acting on both innate and adaptive arms of the immune system. A synergistic antitumor effect was observed by combining anti-LAP antibody with dendritic cell vaccination. To study different LAP+ immune cells on a single-cell level, we developed a 19-panel flow cytometry approach. Based on the TCGA data analysis, the expression of LAP-associated genes correlates inversely with patient survival in a number of cancers. In summary, LAP+ immune cells contribute to cancer progression, and targeting these cells for cancer treatment represents a promising immunotherapeutic approach against cancer. Citation Format: Galina Gabriely, Andre da Cunha, Rafael Rezende, Nathaniel Skillin, Brendan Kenyon, Lena Walton, Murugaiyan Gopal, Howard Weiner. The role of LAP positive immune cells in cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A85.

Glioblastoma (GBM) is an aggressive and incurable brain tumor; its malignancy has been associated with the activity of tumor infiltrating myeloid cells. Myeloid cells play important roles in the tumor control by the immune response, but also in tumor progression. Indeed, GBM exploits multiple mechanisms to recruit and modulate myeloid cells. The Aryl Hydrocarbon Receptor (AHR) is a ligand activated transcription factor implicated in the regulation of myeloid cells. In this review, we will summarize current knowledge on the AHR role in the control of myeloid cells and its impact on GBM pathogenesis.