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.