Biology subjects

Aintablian, A.

Publications and source records attributed to Aintablian, A..

4 recordsLinked to original sources

bioRxiv2026

MYC/MIZ1 suppression of lysosomal protein degradation drives immune evasion in pancreatic ductal adenocarcinoma

The MYC oncoprotein promotes immune evasion of pancreatic ductal adenocarcinoma (PDAC), but the underlying molecular mechanisms are not fully understood. Here we show that MYC protects PDAC tumors from CD4+ T cell-dependent elimination. Single cell sequencing shows that MYC suppression in tumor cells increases amino acid availability and broadly activates amino acid-responsive gene expression programs in immune cell populations. This occurs because MYC-driven uptake depletes free amino acids from tumor interstitial fluid and plasma, while MYC compromises macropinocytosis and autophagy, both of which depend on lysosomal protein degradation. MYC engages the POZ/BTB transcription factor MIZ1 to suppress lysosomal genes regulated by the TFE3/TFEB/MITF network or by free MIZ1, thereby inhibiting lysosomal protein degradation. An orthogonal genetic model enabling transient, selective inhibition of amino acid uptake in tumor cells recapitulates the effects of MYC depletion on amino acid levels in the tumor microenvironment and induces complete, CD4+ T cell-dependent tumor eradication with long-term survival. We propose that MYC-mediated, cell-autonomous disruption of lysosome function coupled to non-cell-autonomous protection from immune clearance allows MYC-low cells to benefit from MYC-high neighbors, such that intratumoral heterogeneity in MYC expression confers a selective advantage to the entire tumor. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/740267v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@140d2ccorg.highwire.dtl.DTLVardef@cf5f1borg.highwire.dtl.DTLVardef@6d132aorg.highwire.dtl.DTLVardef@10535e6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Profound CD4+ T-Cell Reprogramming by Melphalan-Driven Oxidative Stress in High-Risk Multiple Myeloma

T cell-based immunotherapies have become central to the treatment of multiple myeloma (MM), yet their efficacy depends on the functionality of endogenous T cells. How cumulative treatment exposure, particularly high-dose melphalan, together with disease-intrinsic high-risk features shapes T-cell composition and immune competence remains incompletely understood. Here, we analyzed T cell composition and function in bone marrow (BM) and peripheral blood (PB) samples from MM patients across different stages of their treatment journey using flow cytometry (BM, n=162; PB, n=1,733), single-cell RNA sequencing (n=19), and cytotoxicity assays (n=20). We reveal reduced overall T cell frequencies and CD4+/CD8+ T cell ratio, associated with lines of therapy and driven in part by depletion of naive CD4+ T cells in gene-expression defined high risk (HR) disease. Among therapeutic agents, melphalan exerted the strongest effects on T cell populations and induced pronounced redox stress in both T cells and myeloma cell lines. This oxidative stress signature was enriched in HR patients and was reversible with N-acetyl-L-cysteine treatment. Together, these findings identify immune dysregulation as a defining feature of HR MM that extends beyond tumor-intrinsic genomic alterations and is further shaped by treatment-induced remodeling of the BM microenvironment. Given the association between higher CD4+ T cell numbers and improved CAR-T cell outcomes, our data highlight the translational importance of treatment sequencing, particularly in HR MM. One Sentence SummaryMelphalan-induced redox stress depletes CD4+ naive T cells, particularly in patients with high-risk multiple myeloma.

Cancer Biology↗

bioRxiv2026

Glycosylated GM-CSF expands B-1b cells and B-1b plasma cells and programs them for immunosuppression

The myeloid growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) exhibits paradoxical pro- and anti-inflammatory functions, but the factors determining these divergent outcomes remain unclear. Here, we report that this functional divergence is controlled by its glycosylation. Murine recombinant fully glycosylated GM-CSF (rgGM-CSF) specifically induces immunosuppressive cell types, whereas its recombinant non-glycosylated counterpart (rngGM-CSF) promotes effector immune cells. Using single-cell ATAC-sequencing and flow cytometry, we show that rgGM-CSF has a previously unrecognized ability to effectively expand IL-10+ LAG-3+ PD-L1+ B-1b plasma cells (PCs) with immunosuppressive properties and self reactive natural IgM secretion. Although rgGM-CSF also promotes the expansion of hematopoietic stem and progenitor cells (HSPCs) and monocytic myeloid-derived suppressor cells (M-MDSCs), adoptive transfer experiments demonstrate that the rgGM-CSF-induced B-1b PCs are responsible for an IL-10-dependent long-term protection in mice from experimental autoimmune-encephalomyelitis (EAE). Our data suggest that glycosylation enhances the systemic bioavailability and activity of GM-CSF and promotes the expansion of immunoregulatory cells rather than pro-inflammatory myeloid effector cells. Together, these results demonstrate that the dual activity of GM-CSF is controlled by its glycosylation, resulting in opposing immune functions. These findings support a re-evaluation of human rgGM-CSF (regramostim) as a potential therapeutic strategy for immunosuppression in transplantation and autoimmune diseases. Key pointsO_LIGlycosylated GM-CSF promotes B-1b cells and B-1b plasma cells expansion and establishes their long-term imprinting as IL-10+ LAG3+ PD-L1+ natural IgM secreting regulatory cells. C_LIO_LIAlbumin binding enhances the systemic activity of glycosylated GM-CSF in generating regulatory B-1b plasma cells. C_LIO_LIGlycosylated GM-CSF injections into mice expand M-MDSCs, but their suppressive iNOS production is only maintained short-term. C_LIO_LINon-glycosylated GM-CSF injections preferentially promote expansion of pro-inflammatory effector monocytes and neutrophils. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=179 HEIGHT=200 SRC="FIGDIR/small/703206v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1814c57org.highwire.dtl.DTLVardef@1bb0e95org.highwire.dtl.DTLVardef@1ba8011org.highwire.dtl.DTLVardef@12df69f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

MDSC depletion during immunization with heat-killed Mycobacterium tuberculosis increases protection against BCG infection.

Tuberculosis (TB) is still one of the deadliest infectious diseases globally. Although i.d. BCG immunization offers limited protection, a vaccine based on Mycobacterium tuberculosis (Mtb) has yet to be approved. Our previous findings demonstrated that s.c. immunization with heat-killed Mtb significantly increased the number of monocytic myeloid-derived suppressor cells (M-MDSC) in mice. Therefore, we hypothesized that the defense against a subsequent BCG infection would be impaired in Mtb-immunized mice. Surprisingly, mice vaccinated with Mtb were protected against a BCG infection and showed elevated frequencies and activation of DC and mycobacteria-specific T cells despite high frequencies and suppressor activity of M-MDSC. Genetic ablation of CCR2+ monocytic cells or pharmacological intervention with all-trans retinoic acid (ATRA) reduced the frequency of Mtb-induced M-MDSC, enhanced frequencies, and activation of dendritic cells (DC) and CD4+ T cells, and resulted in decreased bacterial loads in the lung and spleen. These findings offer fresh perspectives on TB vaccination using heat-killed Mtb despite parallel unwanted vaccine-induced M-MDSC. M-MDSC depletion by ATRA further tips the balance towards immunity and should be considered an adjunct host-directed therapy with TB vaccines in humans.

immunology↗