PTPN22 (Protein Tyrosine Phosphatase Non-Receptor Type 22)

The current study recognized the most relevant genes involved in the immune system in high-grade serous ovarian cancer. The findings of this study provided a holistic understanding of the tumor microenvironment that can be used for introducing therapeutic targets.

PTPN22's pro-autoimmune variant (C1858T) was found to have a risk preventive association with multiple types of cancer, to contribute to improved overall survival in patients treated with the anti-PD-L1 atezolizumab, and to enhance tumor immunity in mice...With this approach, we identified and advanced fragments that bind PTPN22 at two novel nonorthosteric sites. Due to the shared tertiary structure of the phosphatase domain, we believe this hit finding effort, combined with knowledge about the allosteric circuitry of phosphatases, can provide synergistic value.

In vivo experiments demonstrated that combining curcumin with immune checkpoint inhibition (ICIs) further promotes T cell activation, inhibits Tregs infiltration, and enhances ICIs efficacy against tumor growth. Therefore, PTPN22 represents a therapeutic target for improving T cell exhaustion in RCC and enhance ICIs efficacy through CBL-mediated ubiquitination and degradation of PD-L1.

The analyzed variants in the PTPN22, CD226, and INS genes were overrepresented in pediatric patients with T1D, suggesting potential therapeutic targets for modulating the autoimmune process. Their associations with specific clinical and autoimmune profiles can be applied in the identification of high-risk patients and help optimize their follow-up.

Importantly, PTPN22 knockout abrogated the anti-migratory effects of IRAK-M, confirming its essential role in this pathway. These findings establish the IRAK-M-PTPN22 axis as a critical suppressor of melanoma metastasis within the tumor microenvironment and highlight its potential as a therapeutic target to limit tumor dissemination and improve patient outcomes.

We further show that PEP and its R619W variant distinctly modulate the production of TNFα, IL-12 and IL-2 in DCs following LPS stimulus. Taken together, our results challenge the current understanding of the role of PEP during inflammation while providing new insight into how the PEP-R619W variant may alter myeloid cell function during disease.

We further show that PEP and its R619W variant distinctly modulate the production of TNF-α, IL-12, and IL-2 in DCs following LPS stimulus. Taken together, our results challenge the current understanding of the role of PEP during inflammation while providing new insight into how the PEP-R619W variant may alter myeloid cell function during disease.

Finally, we found that selective, partial inhibition of Itk using Soquelitinib reduced basal CD69 expression in CAR-Jurkat cells while maintaining their ability to activate in response to antigen. These data suggest that TCRζ determines the pY signalling profile and that Itk drives basal activation of CD19-CAR Jurkats, which may impact evaluation of new CAR designs in CAR-Jurkat screens.

Neutrophil adhesion to HUVECs and transmigration through the monolayer were increased in the HET (n = 4) versus WT (n = 6) patients under both basal and TNF-α conditions (p < 0.0001). Neutrophils from C1858T patients are more intrinsically active with increased ROS production and HUVEC adhesion/transmigration, suggesting enhanced contribution to the migration of other immunotypes from vessels into the pancreatic islets during T1D etiopathogenesis.

CD8ΔALK5 OT-I T cells were better able to control tumor clones with moderate TCR agonism compared to WT OT-I T cells. Targeting TGFβ signaling is one approach to enhance TCR signaling following strong or moderate agonism, alter differentiation toward more cytotoxic transitory exhaustion, and reduce terminal exhaustion, to improve antitumor immunity.

Together, these findings position immune evolution as a driver of acquired resistance and identify macrophage-NK cell crosstalk as a therapeutically actionable axis to overcome immune exclusion and improve targeted therapy across multiple cancer types. Cancer therapy resistance emerges from a dynamic evolution of the tumor microenvironment, characterized by macrophage-driven NK cell infiltration during initial tumor regression, followed by exclusion of NK cells during residual disease, highlighting macrophage-NK cell interactions as a promising therapeutic target to improve clinical outcomes.

Finally, we find that selective, partial inhibition of Itk using Soquelitinib reduces basal CD69 expression in Jurkat CAR T cells while maintaining their ability to activate in response to antigen. Our data suggest that the ζ-chain determines the pY signalling profile of CD19-CAR Jurkat T cells and that Itk may drive antigen-independent CD19-CAR activation.