NLRP3 Regulates IL-4 Expression in TOX+ CD4+ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression.

In cutaneous T cell lymphoma (CTCL), a dominant Th2 profile associated with disease progression has been proposed. Moreover, although the production and regulation of IL-4 expression during the early stages of the disease may have important implications in later stages, these processes are poorly understood. Here, we demonstrate the presence of TOX+ CD4+ T cells that produce IL-4+ in early-stage skin lesions of CTCL patients and reveal a complex mechanism by which the NLRP3 receptor promotes a Th2 response by controlling IL-4 production. Unassembled NLRP3 is able to translocate to the nucleus of malignant CD4+ T cells, where it binds to the human il-4 promoter. Accordingly, IL-4 expression is decreased by knocking down and increased by promoting the nuclear localization of NLRP3. We describe a positive feedback loop in which IL-4 inhibits NLRP3 inflammasome assembly, thereby further increasing its production. IL-4 induced a potentially malignant phenotype measured based on TOX expression and proliferation. This mechanism of IL-4 regulation mediated by NLRP3 is amplified in late-stage CTCL associated with disease progression. These results indicate that NLRP3 might be a key regulator of IL-4 expression in TOX+ CD4+ T cells of CTCL patients and that this mechanism might have important implications in the progression of the disease.

Induction of Progenitor Exhausted Tissue-Resident Memory CD8+ T Cells Upon Salmonella Typhi Porins Adjuvant Immunization Correlates With Melanoma Control and Anti-PD-1 Immunotherapy Cooperation.

Immunotherapy has improved the clinical response in melanoma patients, although a relevant percentage of patients still cannot be salvaged. The search for the immune populations that provide the best tumor control and that can be coaxed by immunotherapy strategies is a hot topic in cancer research nowadays. Tumor-infiltrating TCF-1+ progenitor exhausted CD8+ T cells seem to grant the best melanoma prognosis and also efficiently respond to anti-PD-1 immunotherapy, giving rise to a TIM-3+ terminally exhausted population with heightened effector activity. We tested Porins from Salmonella Typhi as a pathogen associated molecular pattern adjuvant of natural or model antigen in prophylactic and therapeutic immunization approaches against murine melanoma. Porins induced protection against melanomas, even upon re-challenging of tumor-free mice. Porins efficiently expanded IFN-γ-producing CD8+ T cells and induced central and effector memory in lymph nodes and tissue-resident (Trm) T cells in the skin and tumors. Porins induced TCF-1+ PD-1+ CD8+ Trm T cells in the tumor stroma and the presence of this population correlated with melanoma growth protection in mice. Porins immunization also cooperated with anti-PD-1 immunotherapy to hamper melanoma growth. Importantly, the potentially protective Trm populations induced by Porins in the murine model were also observed in melanoma patients in which their presence also correlated with disease control. Our data support the use of cancer vaccination to sculpt the tumor stroma with efficient and lasting Trm T cells with effector activities, highlighting the use of Porins as an adjuvant. Furthermore, our data place CD8+ Trm T cells with a progenitor exhausted phenotype as an important population for melanoma control, either independently or in cooperation with anti-PD-1 immunotherapy.

Nlrp1b1 negatively modulates obesity-induced inflammation by promoting IL-18 production.

Obesity-induced inflammation, triggered by lipid-mediated activation of the Nlrp3 inflammasome, results in glucose metabolism alterations and type 2 diabetes. This knowledge has been generated using animals deficient for any of the different components of this inflammasome (Caspase-1, Asc or Nlrp3) in the C57BL/6 background. Unlike C57BL/6 mice, which carry allele 2 of the Nlrp1b gene (Nlrp1b2), Balb/c mice that carry allele 1 (Nlrp1b1) are less prone to develop alterations in the glucose metabolism when fed with a high fat diet. However, the molecular bases for these metabolic differences are unknown. Here we show that the Nlrp1b1 allele down regulates the adipose tissue inflammatory response attenuating glucose intolerance and insulin resistance in obese C57BL/mice. Our results indicate that the positive effects of the Nlrp1b1 inflammasome on glucose tolerance and insulin sensitivity involve IL-18-mediated effects on lipolysis, pointing out that differential expression of allelic variants of genes coding for inflammasome components might control susceptibility or resistance to develop diabetes in obese individuals.