CXCL9 expression

We identify IFNϵ loss as the elusive 9p21 link to human immune-cold, CXCL9/10-CXCR3 axis-depleted tumors. Extending mouse-model studies of IFN-I on TME immune-cell levels, we found that IFNϵ loss is the primary cell-intrinsic 9p21 immune signal to DC and macrophage subtype and subcluster expression of CXCL9 and CXCL10, the major sources of these chemokines. Larger deletions to 9p24 further restrict CXCL9/10 induction via loss of IFN-γ-pathway gene, JAK2. 9p-loss tumors with these distinct IFN defects operative in the TME, lack the capacity of endogenous CXCL9/10 induction in an immune-desert, ICT-resistant state. These data, the extensive 9p loss/ICT resistance body of evidence, and early NSCLC DC-chemokine vaccine trials, have led to a DC vaccine engineered with a CXCL9/10 payload, designed to bypass the specific, severe chemokine deficit in 9p loss tumors.

Enhancing IFN-I cytokine production and blocking PGE2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.

In human cancers, a CD206Replete, but not a CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, cDC1, and NK signatures and was associated with better survival. These findings negate the unqualified classification of CD206+ "M2-like" macrophages as immunosuppressive.

Depleting Tregs led to enhanced tumor control in combination with anti-PD-1 and KRAS-G12C inhibitor. Combining Treg depletion with KRAS inhibition shows therapeutic potential for increasing antitumoral immune responses.

The LR model obtained AUC values of 0.771 and 0.724 in the training and validation sets, respectively. The utilization of MRI radiomic features for predicting CXCL9 expression level provides a novel non-invasive approach for breast cancer Prognostic research.

Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC.

Notebly, PDAC patients with lower SIN3B expression showed a more favorable response to anti-PD1 therapy. The findings suggest that targeting SIN3B can enhance cytotoxic T cell infiltration into the tumor site and improve immunotherapy efficacy in PDAC, offering potential avenues for therapeutic biomarker or target in this challenging disease.

Endosialin could inhibit CD8+ T cell infiltration by inhibiting the expression and secretion of CXCL9/10 in CAFs, thus promote HCC progression. Combination therapy with endosialin antibody could increase the antitumor effect of PD-1 antibody in HCC, which may overcome the resistance to PD-1 blockade.

Our study illustrates that the tumor immune microenvironment prior to CPI treatment can be indicative of response. In perspective, modulating the myeloid and/or effector cell compartment by altering the described cell interactions and transitions could improve immunotherapy response.

The seven-gene signature holds promise as a valuable tool for decision-making and prognosis prediction in patients with ovarian cancer.

Finally, using The Cancer Genome Atlas database, we found that XCL1 expression was positively correlated with tumor-infiltrating cDC1s and a better prognosis in melanoma patients. Collectively, our findings provide a novel therapeutic approach to enhance tumor-specific CTL responses through the selective recruitment of CXCL9-expressing cDC1s into the tumor masses.

With this strategy, it is efficient encapsulation and release of multiple drug loads that can efficiently induce CXCL9 expression in macrophages, both in vitro and in vivo in a mouse tumor model. These observations provide a window into the molecular features that define TAM-specific states, an insight a novel therapeutic anticancer approach is used to discover.

Symptomatic BPH with immune-enriched landscapes may support anti-tumor immunity. RNA sequencing of benign prostate biopsy tissue showing upregulation of NKX3-1 and HOXB13 with the absence of T-cells might help in identifying men at higher risk of future PCa development, which may be useful in determining ongoing PCa screening.

Such data suggest these cells might also increase immunosuppressive interactions with T cells. In summary, our study reveals how ICB affects the spatial architecture and crosstalk of different cell types within melanoma brain metastases and will provide insights into new therapeutic strategies for brain metastases patients.

Background: Cevostamab is an FcRH5 (Fc receptor-homolog 5) targeted T cell-dependent bispecific (TDB) currently being evaluated in the clinic, with promising activity and favorable safety profile as a monotherapy in patients (pts) with heavily pre-treated Relapsed/Refractory multiple myeloma (MM) (NCT03275103, Trudel et al... We first examined the T cell compartment by scRNA-seq profiling. Upon FcRH5 TDB treatment, clustering analysis suggested that CD4 and CD8 T cells undergo extensive transcriptional changes compared to control TDB (Fig 1A). A TNF and LTA-expressing CD4 memory cluster was enriched upon treatment in both SoRs and Rs, but to a greater extent in Rs.

P2, N=50, Completed, Emma Guttman | Active, not recruiting --> Completed

Conclusions We identified CCL2 and galectin-3 as tumor factors regulated by K17 expression. Validation studies are needed to confirm their protein expressions and their direct role in tumor-macrophage communications.

Whereas MC1R activation is restricted to melanoma, GNAS activation by hotspot mutations is observed across diverse cancer types and is associated with reduced CXCL9/10/11 expression. Our study implicates MC1R as a melanoma immunotherapy target and suggests GNAS-PKA signaling as a pan-cancer oncogenic pathway inhibiting antitumor T cell response.

The analyses from TCGA cohort (n=138) showed that elevated CXCL9 expression correlated with increased infiltration of B-cells, macrophages, natural killer cells, monocytes and increased expression of immune checkpoint molecules and other CXCL family members, including CXCL10 and CXCL11. These findings confirm the regulatory role of CXCL9 in antitumor immunity and suggest a potential role in treatments involving immune-checkpoint blockade.

In patients with OC, the radiomics signature(RS) of CT scans can distinguish the level of CXCL9 expression and predict prognosis, potentially fulfilling the ultimate purpose of precision medicine.

P=N/A, N=20, Recruiting, Centre Hospitalier Universitaire de Nice | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

This study ascribes for a new immunomodulatory role for IL11 during tumor development that is amenable to anti-cytokine based therapy of colon cancer.

This coordinated chemokine switch led to increased T-cell infiltration in an in vitro chemotaxis assay. Our study demonstrates that CAFs have a phenotypic plasticity that allows their adaptation to contrasting immune tissue microenvironments.

This chemokine system is also likely to contribute to tissue necrosis, which is a signature histological feature of DLBCL-CI. Further studies are warranted to determine whether the CXCL9-CXCL10/CXCR3 axis exerts antitumor effects in DLBCL-CI.

This coordinated chemokine switch led to increased T-cell infiltration in an in vitro chemotaxis assay. Our study demonstrates that CAFs have a phenotypic plasticity that allows their adaptation to contrasting immune tissue microenvironments.

Moreover, specific co-expression of CXCL9 and αPD-L1 in various tumor cells is achieved by replacing the tyrosinase promoter of NP with a survivin promoter, which increases T-cell infiltration and activation and therapeutic efficacy in multiple tumors in female mice. This study provides a strategy to maximize the immunotherapeutic outcome regardless of the heterogeneous tumor microenvironment.

Overexpressed CXCL9 correlates with antitumor immunity and is predictive of a favorable prognosis in UCEC. It hinted that CXCL9 may serve as an independent prognostic biomarker or therapeutic target in UCEC patients, which augmented anti-tumor immune effects to furnish survival benefits.

In T-cell acute lymphoblastic leukemia, chidamide may increase the concentration of CXCL9 in the tumor microenvironment by up-regulating the expression of CXCL9 in tumor cells, leading to an increase in the number of CD8 T cells.

P=N/A, N=20, Recruiting, Centre Hospitalier Universitaire de Nice | Trial primary completion date: Jun 2023 --> Dec 2024

Therefore, RT potentially activates CD8 T cells by inducing IFNs-mediated CXCL10 and ICAM-1 expression in tumors to enhance CD8 T-tumor adhesion and recognition. This study clarified the possible mechanisms of RT and IFNs in regulating CD8 T cell activation in lung cancer.

These findings indicate that CXCL9 is a potential clinical biomarker of prognosis and immunotherapy efficacy for TNBC patients. Also, it stimulates JAK/STAT activity, which in turn modifies the tumor microenvironment.

Glioma cell proliferation and invasion could be inhibited by silencing of CXCL9. Overall, CXCL9 is correlated to the prognosis of glioma patients and may accelerate glioma development via immune regulation.

High CXCL9 expression correlated with increased infiltration levels of immune cells in the TME, including CD8+ T lymphocytes and M1 macrophages. These findings suggest that high PD-L1 expression is a prognostic factor of early-stage CRC, and CXCL9 may play a key role in regulating PD-L1 expression.

SRC-3 is a critical immunomodulator in breast cancer, generating a protumor immune microenvironment. SRC-3 inhibition by SI-2 or SRC-3 KD activates the Cxcl9/Cxcr3 axis in breast tumors and enhances the antitumor immune microenvironment to suppress breast cancer progression.

We hypothesized that the combination of CKM with paclitaxel will promote selective CTL infiltration into TNBC, and along with doxorubicin/cyclophosphamide (AC), will result in higher rate of pCR, translating into improved RFS and OS. The treatment was well-tolerated and no DLTs were observed and we determined RP2D for future studies. We observed promising clinical activity with pCR + ypTmic rate of 66%, comparable to pembrolizumab combination with NAC. A larger phase II study is being designed to confirm the observed efficacy and to determine if CKM regimen would be a safer short-term alternative to pembrolizumab or if CKM can overcome the resistance to the standard pembrolizumab/NAC therapy.

A wide characterization (chemokine receptors, factors involved in pancreatic organogenesis, markers of epithelial-mesenchymal transition, and secretome) revealed that the degree of stemness was associated with KRT19 and NKX2.2 mRNA expression, with CD49a and CA19.9/Tie2 protein expression, and with the secretion of VEGF, IL-7, IL-12p70, IL-6, CCL3, IL-10, and CXCL9. The expression of stem cell markers was also evaluated on primary tumor cells from 55 PDAC patients who underwent pancreatectomy with radical intent, revealing that CXCR4/CD133 and CD24 cells, but not ESACD24CD44, are independent predictors of mortality.

Our results demonstrate that intratumoral administration of PC7A nanovaccine achieved stronger antitumor immunity and efficacy over subcutaneous injection. These data suggest intratumoral administration should be included in the therapeutic design in the clinical use of nanovaccine.

CXCL9 is a driver of successful ICB in preclinical ovarian cancer. Besides being a feasible predictive biomarker, CXCL9-inducing agents thus represent attractive combination partners to improve ICB in this cancer entity.

P=N/A, N=20, Recruiting, Centre Hospitalier Universitaire de Nice | Not yet recruiting --> Recruiting | Trial completion date: Jan 2024 --> Dec 2024 | Initiation date: Jul 2021 --> Dec 2021 | Trial primary completion date: Jul 2021 --> Jun 2023

Interestingly, we observed a high concordance between mouse and human myeloid cells from ours and publicly available scRNA-Seq data. Our data and analysis provide the first translational mouse-to-human atlas of myeloid cells in HNC, providing a way to inform biomarkers and immunotherapeutic targets for potential ICI therapy success in HNC and other cancer types.