ABSTRACT
Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.
Subject(s)
Drug Screening Assays, Antitumor , Immunotherapy , Melanoma/pathology , Melanoma/therapy , Animals , Antineoplastic Agents, Immunological/therapeutic use , CTLA-4 Antigen/immunology , Cells, Cultured , Disease Models, Animal , Drug Screening Assays, Antitumor/methods , Female , Gene Expression Regulation, Neoplastic/drug effects , Genetic Heterogeneity , Humans , Immunotherapy/adverse effects , Immunotherapy/methods , Ipilimumab/therapeutic use , Melanoma/diagnosis , Melanoma/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Prognosis , Programmed Cell Death 1 Receptor/immunology , RNA-Seq , Treatment Outcome , Whole Genome SequencingABSTRACT
A paradox of tumor immunology is that tumor-infiltrating lymphocytes are dysfunctional in situ, yet are capable of stem cell-like behavior including self-renewal, expansion, and multipotency, resulting in the eradication of large metastatic tumors. We find that the overabundance of potassium in the tumor microenvironment underlies this dichotomy, triggering suppression of T cell effector function while preserving stemness. High levels of extracellular potassium constrain T cell effector programs by limiting nutrient uptake, thereby inducing autophagy and reduction of histone acetylation at effector and exhaustion loci, which in turn produces CD8+ T cells with improved in vivo persistence, multipotency, and tumor clearance. This mechanistic knowledge advances our understanding of T cell dysfunction and may lead to novel approaches that enable the development of enhanced T cell strategies for cancer immunotherapy.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immune Tolerance , Lymphocytes, Tumor-Infiltrating/immunology , Neoplasms/immunology , Potassium/metabolism , Stem Cells/immunology , Acetyl Coenzyme A/metabolism , Acetylation , Animals , Autophagy/immunology , Caloric Restriction , Cell Differentiation/genetics , Epigenesis, Genetic , Histones/metabolism , Humans , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Tumor MicroenvironmentABSTRACT
The aim of this study was to synthesize a series of mono-, di- and trisubstituted derivatives of the human African trypanosomiasis drug eflornithine (alpha-difluoromethylornithine, DMFO, CAS 70052-12-9) to determine their partition coefficients, and to assess whether they deliver the parent drug in the plasma. If increased plasma concentrations of eflornithine could be achieved in this way, an oral dosage form would be possible. The derivatives, nine in total, were successfully synthesized by multi-step derivatisation of eflornithine on either its alpha-carboxylic or/and alpha-amino or/and delta-amino groups by either esterification or/and amidation or/and carbamylation, and their structures confirmed by NMR and MS spectroscopy. The majority of derivatives were more lipophilic than eflornithine with log D values in phosphate buffer solution (pH 7.4) ranging from -1.34 to 1.59 (vs. -0.98 for eflornithine). The in vivo absorption after oral administration to Sprague-Dawley rats showed that no derivative delivered eflornithine in the plasma, indicating that the derivatives were either not absorbed from the gastrointestinal tract or not metabolized to the parent drug. Two of the monosubstituted activities were toxic for T. brucei blood stream forms.
Subject(s)
Eflornithine/analogs & derivatives , Eflornithine/blood , Trypanocidal Agents/blood , Animals , Biological Availability , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Indicators and Reagents , Isomerism , Lipids/chemistry , Magnetic Resonance Spectroscopy , Male , Rats , Rats, Sprague-Dawley , Solubility , Trypanosoma brucei brucei/drug effectsABSTRACT
CsgD and cyclic-3',5'-di-guanylate are key regulators of biofilm formation in Salmonella enterica serovar Typhimurium. Our results show that polynucleotide phosphorylase and NlpI oppositely altered expression of CsgD. Polynucleotide phosphorylase and NlpI also had opposite effects on the expression of yjcC, which codes for a cyclic-3',5'-di-guanylate phosphodiesterase affecting CsgD expression.
