IFNG-L

P1, N=28, Active, not recruiting, Jonsson Comprehensive Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Apr 2025 --> Apr 2026 | Trial primary completion date: Apr 2024 --> Apr 2025

The top five most important features contributing to the random forest model were Sulfidibacter, Prestia, Cutibacterium, Acinetobacter and Rhizobium. This study is the largest to date that characterize the tumor microbiota of an Asian cohort of breast cancers, where Sulfidibacter and Priestia, both relatively new and uncharacterized bacteria, were differentially abundant among patients with high vs low immune scores.

Worse survival outcomes in pbDMG patients when comparing high versus low TGFB2 levels in the context of low IFNGR2 levels suggest that the abrogation of the TGFB2 mRNA expression in the immunologically cold tumor microenvironment can be used to treat pbDMG patients. Furthermore, pbDMG patients with low levels of JAK1 or STAT1 mRNA expression in combination with high levels of TGFB2 also exhibited poor OS outcomes, suggesting that the inclusion of (interferon-gamma) IFN-γ to stimulate and activate JAK1 and STAT1 in anti-tumor APC cells present the brainstem TME can enhance the effect of the TGFB2 blockade.

"miR-181a is a key factor controlling the STING pathway and driving PARPi and platinum-based drug resistance in TNBC and OvCa. The miR-181a-STING axis can be used as a potential marker for predicting PARPi responses in TNBC and OvCa tumors."

Cibersort analysis2 showed that gamma delta T cells (-52%), activated memory CD4 T cells (-50%), activated NK cells (-29%), CD8 T cells (-21%) demonstrated the most significant reductions in TFI-high. Conclusions Tumor with high fragmentation, or TFI-high is closely correlated with high fibroblast infiltration, low IFNG signature-related NK and T cells infiltration, but has minimal impact on overall densities of lymphocytes and macrophages, as well as PD-1/PD-L1 and CTLA4/CD28 axes.

Table: 1121P Conclusions Our results suggest that the IFNg-signature could become a biomarker for treatment decisions in LDH low patients directing towards anti-PD1 monotherapy (in IFNg high patients) versus combination therapy, with either anti-LAG3 or anti-CTLA-4 in IFNg low patients. However, confirmation in larger cohorts and in other combination therapies is needed.

To determine if neurons respond to in a cell-autonomous manner, we produced mutant mice with a deletion of the IFN-γ-binding domain of IFNGR1 only in dopaminergic neurons, which resulted in a complete loss of dopaminergic neuronal response to IFN-γ. Our results demonstrate that neurons can respond to IFN-γ in a cell-autonomous manner by upregulating MHC-I and its related genes in vivo, although the expression level is low compared to oligodendrocytes, astrocytes, and microglia.

PDO model intra-tumoral and inter-patient heterogeneity in the tumor-immune phenome and IFNg responsivity. Our paired autologous PDOT biobank enables patient-specific identification of targetable immune checkpoints and PDOT co-cultures enable characterization of patient-specific anti-tumor response to rationally design ICI combination therapies that augment anti-tumor T cell responses in RCC.

PD-L1/Clever-1 IHC staining ratio may be used to predict bexmarilimab responding patients. These patients have a low PD-L1 staining and low IFNg levels as reported previously, and are often refractory to checkpoint inhibitors and other T cell activating agents. Bexmarilimab provides a novel therapy option for a tumor group that is otherwise poorly responsive to immune therapies.

In live imaging experiments, we found that blocking ERK activity with the ERK inhibitor Ulixertinib blocks the induction of cell death after IFNg treatment in 17 of 23 (~74%) IFNg-sensitive PDM lines covering all the MAPK mutant and triple wildtype molecular subtypes of melanoma...This pathway is active in all melanoma subtypes, making it an attractive target to enhance IFNg GI in tumor cells. Our results provide a new understanding of the IFNg GI pathway that will also be crucial to define mechanisms of GI resistance in tumor cells.

IFN-g release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunological landscape toward Treg induction, contributing to an immunotolerant microenvironment.

Conclusions TIL expanded from STS demonstrate greater tumor-specific functional capacity and cytotoxicity after CD8 enrichment and CD69+ FACS compared to bulk expanded TIL. These data validate the strategy to enhance CD8+CD69+ TIL during culture to yield a more efficacious cellular immunotherapy product.

Moreover, the IFNGrGS score had solid prognostic value and the potential to screen ICB and radiotherapy sensitive populations. Collectively, our study provided insights into the role of IFNG on the GBM immune microenvironment and offered feasible information for optimizing the treatment of GBM.

Our scRNA-seq data confirmed luminal subtype predominance and described the heterogeneous TME in UTUC. The statistically significant relationship of tumor cell IFNg with increased overall immune cell infiltration is notable and may have implications for systemic therapy response. Further high-resolution studies are needed to expand our knowledge of the molecular biology and TME of UTUC with implications for treatment selection and disease surveillance.