Acute heart allograft rejection remains a major barrier to long-term transplant survival, yet the mechanisms by which environmental factors influence recipient alloimmunity remain poorly understood. Clinical observations have suggested improved transplant outcomes at higher elevations, but the underlying biology has not been established. Here, using a murine heterotopic heart transplantation model, we demonstrate that recipient, but not donor, hypoxic preconditioning significantly prolongs heart allograft survival, and that pre-transplant hypoxic exposure alone is sufficient to confer this benefit. Single-cell RNA sequencing of recipient peripheral blood mononuclear cells revealed that chronic hypoxia suppresses antigen presentation programs while enriching tolerance-associated transcriptional signatures and remodels the circulating myeloid compartment toward non-classical monocytes. Pharmacologic inhibition of hypoxia-inducible factor 2α (HIF2α) with belzutifan abolished the survival advantage conferred by recipient hypoxia, demonstrating that HIF2 activity is required for this protective immune adaptation. Together, these findings identify chronic recipient hypoxic conditioning as a previously unrecognized regulator of innate immune remodeling and suggest that therapeutically promoting a hypoxia-induced tolerogenic monocyte state may represent a strategy to improve heart transplant outcomes. This study identifies chronic recipient hypoxic conditioning as a previously unrecognized regulator of innate immune remodeling and suggests that promoting a hypoxia-induced tolerogenic monocyte state may improve heart transplant outcomes. This study identifies chronic recipient hypoxic conditioning as a previously unrecognized regulator of innate immune remodeling and suggests that promoting a hypoxia-induced tolerogenic monocyte state may improve heart transplant outcomes.
DNA mismatch repair deficiency (MMRd) causes hypermutation and increased T cell response in multiple tumor types. MMRd colorectal cancers (CRC) display frequent immune evasion, but respond to immune checkpoint blockade (ICB), through uncertain mechanisms. We generated mouse models of MMRd CRC, and found that accelerated tumorigenesis was accompanied by loss of major histocompatibility class I (MHC-I) expression and exclusion of cytotoxic CD8+ T cells, but not helper CD4+ T cells. MHC-I deletion (MHC-IKO) in a syngeneic MMRd CRC model reduced tumor CD8+ but not CD4+ cell infiltrate, and accelerated tumor growth. MMRd MHC-IKO tumors were resistant to anti-PD1 ICB, but sensitive to anti-PD1 and anti-CTLA4 combination ICB (cICB) with response dependent on both CD4+ and CD8+ T cells, but not γδ-T cells. CD4+ cell depletion-induced cICB resistance was reversed by CD40 agonism, suggesting that CD4+ cells directly or indirectly license CD8+ cell for MHC-I-independent cytotoxicity. Investigation of MHC-I status as predictor of cICB vs ICB monotherapy appears worthwhile. DNA mismatch repair-deficient (MMRd) colorectal cancers (CRCs) commonly lose MHC-I expression yet remain sensitive to immune checkpoint blockade, suggesting alternative mechanisms sustain antitumour immunity. Understanding these could reveal new response biomarkers and therapeutic targets. DNA mismatch repair-deficient (MMRd) colorectal cancers (CRCs) commonly lose MHC-I expression yet remain sensitive to immune checkpoint blockade, suggesting alternative mechanisms sustain antitumour immunity. Understanding these could reveal new response biomarkers and therapeutic targets.
An immunosuppressive microenvironment limits therapeutic efficacy in melanoma. Beyond T-cell abundance and function, tumor control depends on T-cell access to malignant cells, yet the vascular mechanisms governing T-cell positioning remain poorly defined. Using RNA sequencing of endothelial cells from tumor cores versus peripheries in a mouse melanoma model, we identified intercellular adhesion molecule-1 (ICAM-1) as a candidate regulator of T-cell localization. During tumor growth, T cells shifted from a balanced core-margin distribution to marked exclusion from the core, particularly in T cell-inflamed tumors. This spatial polarization, less evident in other immune subsets, coincided with high expression of lymphocyte function-associated antigen-1 (LFA-1) on T cells. Endothelial ICAM-1 became enriched at the tumor periphery, where vascular integrity was compromised, with increased vascular leakage and reduced pericyte coverage. ICAM-1 blockade restored T-cell infiltration, enhanced effector activity, and delayed growth of immunogenic tumors, and sensitized an immune-refractory tumor to anti-PD-1 blockade. These findings identify endothelial ICAM-1 as a vascular determinant of T-cell positioning and the ICAM-1/LFA-1 axis as a modifiable checkpoint to enhance antitumor immunity and immunotherapy efficacy. Endothelial ICAM-1 was identified as a spatial regulator of T-cell exclusion from the tumor core in melanoma. ICAM-1 blockade increased T-cell infiltration, enhanced effector activity, and delayed growth of immunogenic tumors, while also sensitizing immune-refractory tumors to anti-PD-1 blockade. Endothelial ICAM-1 was identified as a spatial regulator of T-cell exclusion from the tumor core in melanoma. ICAM-1 blockade increased T-cell infiltration, enhanced effector activity, and delayed growth of immunogenic tumors, while also sensitizing immune-refractory tumors to anti-PD-1 blockade.
Pathogenic, bi-allelic variants in RMND1 typically manifest as an early-onset multisystemic mitochondrial disease, yet the consequences of RMND1 dysfunction in vivo remain poorly understood. To answer this question, we generated and characterized the first in vivo model of RMND1-related disease, carrying the recurrent p.(Asn238Ser) variant. Homozygous Rmnd1N238S mice exhibit growth defect, premature mortality, and a multisystem phenotype marked by widespread tissue-dependent defects in oxidative phosphorylation assembly and activity. Quantitative proteomic analysis of Rmnd1N238S heart revealed extensive metabolic remodeling, with significant alterations in the abundance of mitoribosomal proteins and factors associated with mitoribosome maturation. Selected changes in mitoribosomal protein abundance were also observed in Rmnd1N238S liver, and RMND1 mutant and depleted human cells. Despite these changes, sucrose-gradient sedimentation did not reveal a gross alteration in mtSSU, mtLSU, or 55S distribution, suggesting that RMND1 dysfunction perturbs mitoribosomal protein homeostasis that could affect late-assembly stages of the mitochondrial ribosome large subunit. Together, our findings establish Rmnd1N238S mice as a robust in vivo model of RMND1-related disease and provide a framework for understanding how RMND1 supports mitochondrial gene expression. RMND1 is a highly conserved protein of unknown function associated with human mitochondrial protein synthesis defects. We generated and characterized the first Rmnd1 knock-in mouse, which carries the missense mutation p.(Asn238Ser), reported in several patients. RMND1 is a highly conserved protein of unknown function associated with human mitochondrial protein synthesis defects. We generated and characterized the first Rmnd1 knock-in mouse, which carries the missense mutation p.(Asn238Ser), reported in several patients.
