• Fibroblasts are key immune sentinel cells that can both support and suppress immunity.
• Fibroblasts are heterogenous, plastic, and can shift between states dependent on local stimulus.
  
• Tumours rich in myofibroblastic cancer-associated fibroblasts (myCAF) are associated with poor prognosis, CD8 T cell exclusion, and resistance to checkpoint immunotherapy.
  
• Given fibroblast plasticity, switching fibroblasts from immune-suppressive to immune-supportive phenotypes is an attractive therapeutic strategy.

Immune-checkpoint inhibitors (ICIs) have shown therapeutic efficacy in various solid tumours; however, ICIs have not shown clinical efficacy in hematological cancers such as AML and MM. Our findings suggest that combined blocking of previous ICIs with CD96 in T cells and controlling PRRX1 levels in CAF may be beneficial for therapy.

A FAP-targeted bispecific antibody agonizing the Lymphotoxin Beta receptor for the modulation of the tumour microenvironment to induce the formation of HEV-rich immune niches will be introduced. LTBR pathway activation enhances the expression of adhesion molecule and chemoattractants, induces high endothelial venule formation, and the build-up of immune cell niches up to tertiary lymphoid structures, thus enabling CPI's anti-tumour efficacy. The IND-enabling preclinical data package will be summarized.

Agonistic antibodies directed to immunostimulatory receptors are an untapped source for immunotherapy. Here we discuss the properties required to optimally agonise these receptors and describe potential strategies for leveraging them for immune activation and anti-tumour efficacy in the complicated environment of the tumour. Using TNFR superfamily receptors as a paradigm and IgSF members for comparison, we evaluate the multiple methods for delivering powerful receptor agonism.

Prostanoids have long been known as players suppressing tumour immunity, but their exact mode of action remained unknown. In fact, large trials have probed systemic synthesis inhibition for cancer prevention and therapy with mixed results. We could recently demonstrate that PGE2 suppresses CD8+T cells in the TME to curtail anti-tumour immunity, showcasing the need for tailored interventions. We will discuss and present novel approaches how this could be achieved.

Immune Checkpoint Inhibition (ICI) remains ineffective in a significant proportion of metastatic melanoma patients. Immune profiling of the melanoma Tumour Microenvironment pre-treatment using high-plex imaging and RNA sequencing revealed that monocyte-derived macrophage (MDM) and T cell recruitment associates with anti-PD1 therapy response and survival. This study provides important clues for future precision combination therapy strategies.

This presentation will explore the emerging evidence on the role of neutrophils in anti-tumour immunity. It will discuss recent findings challenging the traditional view of neutrophils as bystanders or tumour-promoting cells. The focus will be on elucidating the multi-faceted functions of neutrophils in modulating the tumour microenvironment, mediating tumour cell killing, and regulating adaptive anti-tumour immune responses. Therapeutic strategies harnessing the anti-tumour potential of neutrophils will also be discussed.

Today all antibodies approved in the clinic are based on IgG. We investigate the therapeutic potential of IgA in oncology, since IgA has the unique capacity to activate neutrophils to kill cancer cells. In the presentation we will show how neutrophils can kill cancer cells, and why they do this much better than IgG antibodies. We engineered IgA for a better production, stability, and half-life. Block of myeloid checkpoints like CD47 will further enhance IgA activity. Effectivity of IgA in several pre-clinical models will be shown.

Certepetide, an internalising RGD peptide, is a novel investigational drug that selectively actuates the CendR active transport mechanism to optimise the penetration of anti-cancer drugs through the stroma of solid tumours. Importantly, certepetide also has profound tumour microenvironment modifying properties. It depletes intratumoural immunosuppressive cells, recruits cytotoxic T cells, and inhibits the metastatic cascade. Validating preclinical and clinical data in pancreatic ductal adenocarcinoma and other solid tumours will be presented.

As the most prevalent immune cell within the tumour microenvironment (TME), macrophages are implicated in tumourigenesis and metastasis. However, these cells can be harnessed for cancer therapy. In this talk we will discuss the potential of IgE class antibodies directed to cancer cells can restrict tumour growth, promoting macrophage stimulation ad pro-inflammatory conditions in the TME.

Based on the extensive work in preclinical models and clinical trials several cancer immune based therapies, such as immune checkpoint blockade and adoptive T cell therapies have been approved. However, their benefit in many cancers remains limited as patient present with primary or acquired resistance to these therapies. We will be addressing the critical limitations, and mechanisms of resistance to immune-based cancer therapies. We will discuss tumour microenvironmental factors and immune evasion strategies employed by tumours. We will highlight strategies to overcome resistance, such as combination approaches, novel targets, and strategies to modulate the tumour microenvironment.

Aakha Biologics is developing first-in-class MICA X TAA bispecific antibodies for solid tumours that combines multiple mechanism of action into a single agent, bringing synergy in NK cell activation and subset of T cells (gamma delta T cells, CD8 T cells, and NKT cells). The target MICA is selectively expressed on multiple solid and liquid tumours, making it an ideal target for pan cancer indications.

The development of immunotherapeutic agents has transformed the treatment of neuroblastoma patients. Nevertheless, the efficacy of these immunotherapies is challenged by the highly immunosuppressive microenvironment, which hampers immune cell migration into tumor area. Here, we aim to identify targeted strategies to enhance immune cell infiltration, by mapping the tumor immune microenvironment (TIME) and cell-cell interactions in neuroblastoma using imaging mass cytometry (IMC).