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Keynote Speakers

Julian Downward, Francis Crick Institute, UK
https://www.crick.ac.uk/research/find-a-researcher/julian-downward

Targeting the interplay between oncogenic RAS signaling and tumour immune evasion in lung cancer
Drugs have been developed that target mutant forms of the KRAS major oncogenic driver protein, but while these agents have impressive short-term clinical effects on tumours bearing these mutations, long-term impact is rapidly compromised by the development of drug resistance. This has led to great interest in combining KRAS inhibitors with other modalities to improve the durability of responses, with particular emphasis given to immunotherapies, which can be effective in some cancers, including lung cancer.

Oncogenic KRAS signaling not only promotes the proliferation and survival of cancer cells, but can also play a major role in suppressing anti-tumor immunity through several mechanisms, including secretion of cytokines and chemokines, reduction of antigen presentation and suppression of tumour-intrinsic interferon responses. Consequently, treatment with KRAS inhibitors alleviates oncogenic KRAS driven immune suppression, resulting in a profound remodelling of the tumour microenvironment, which we have analysed in mouse lung cancer models using a range of spatial, multiomic and single cell methodologies.
Using different mouse lung cancer models that we have developed and optimised to mimic the main tumour microenvironment immune phenotypes seen in the clinic, we can see impressive combination effects of KRAS inhibitors and PD-1 directed immunotherapies in the most immunogenic tumours, leading to their complete eradication dependent on the immune system. However, in immune cold tumours, distinct cellular communities can be identified that constrain the ability of these combinations to unleash immune attack on the tumour. Multiple layers of immune evasive behaviour can be identified, with regulatory T cells playing a particularly critical role. Combination targeting of Tregs along with KRAS shows considerable potential for treatment of common forms of lung cancer.

Jana de Boniface, Clinical Professor, Dept. of Medical Epidemiology and Biostatistics, Karolinska Institutet Breast surgeon, Capio St. Göran's Hospital, Stockholm Sweden
https://ki.se/en/research/research-areas-centres-and-networks/research-groups/breast-cancer-surgery-jana-de-bonifaces-research-group

Right-sizing strategies for the management of axillary lymph node metastases in breast cancer
In the recent decades, locoregional management in individuals with breast cancer has been revolutionised. With new systemic therapies being introduced at a staggering speed, the door to less extensive surgical management is wider open, allowing us to significantly reduce patients’ risk of debilitating long-term postoperative morbidity. While a full axillary lymph node dissection (ALND), removing at least 10 lymph nodes from the axilla, was the only axillary surgery available for many years, the implementation of the sentinel lymph node (SLN) biopsy more than 20 years ago paved the way for refined, less extensive yet more precis staging surgery. In primary surgery, several trials have questioned the role of completion ALND in the case of metastases in the SLN biopsy, and limits are still being pushed on the way to find the right balance between local control, providing relevant staging information and maintaining excellent oncological outcomes. In the neoadjuvant setting, ALND performed after systemic therapy comes with an even higher risk of morbidity regarding the arm and shoulder. Here, new surgical strategies include the marking and selective removal of metastases identified at diagnosis, and the stepwise down-scaling of the use of ALND. The future of locoregional management lies in the identification of the right-sized surgical approach for each individual.

Research area: breast cancer, axillary surgery

Anna Blom, Lund University, SE
https://www.protein-chemistry.lu.se

Unexpected roles of complement regulators in cancer development
Complement inhibitors have traditionally been considered as regulators of innate immune homeostasis, preventing excessive complement activation and tissue damage. However, recent discoveries revealed unexpected roles for these molecules in shaping the tumor microenvironment.

This presentation will focus on two unexpected players - Factor H (FH) and Cartilage Oligomeric Matrix Protein (COMP) - and their impact on cancer immunity.

Factor H, a key complement inhibitor, has been found to interact with the ICOS receptor on regulatory T cells (Tregs) in glioma, promoting their survival and immunosuppressive function. Additionally, FH contributes to the formation of an immunosuppressive tumor microenvironment by guiding monocyte differentiation toward macrophages with suppressive properties, further restricting anti-tumor immune responses.

Meanwhile, COMP, traditionally linked to cartilage integrity where it also regulates complement mediated inflammation, has emerged as an oncogene in multiple cancers, including breast, colorectal, and pancreatic cancer. High COMP expression in tumors is associated with increased fibrosis, immune exclusion, and activation of tumor-promoting pathways, all of which contribute to resistance against conventional and immunotherapies.

Together, these findings challenge conventional views of complement regulation in cancer and highlight FH and COMP as critical modulators of immune evasion. Understanding their roles may provide new strategies for targeting immune resistance in tumors, with the potential to enhance current cancer therapies and improve patient outcomes.

Douglas Hanahan, Lausanne Branch, Ludwig Institute for Cancer Research, and EPFL, CH
https://agora-cancer.ch/laboratory/hanahan-lab/

Immunosuppression in the tumor microenvironment, and beyond
The natural history of multistep tumorigenesis commonly involves the acquisition, at one stage or another, of the hallmark capability for avoiding (T-cell-mediated) immune destruction.  Important principles of immune evasion have come from investigation of tumor phenotypes in immunocompetent models of cancer, and two will be presented.

The first involves variable expression of a neuronal RNA binding protein, FMRP, in most solid tumor types. FMRP regulates mRNA stability and translation of hundreds of genes, amongst its diverse functions. A gene signature indicative of its regulatory activity in cancer cells correlates with worse outcome across human cancers, and with comparatively poorer responses to checkpoint immunotherapy.  Genetic disruption of FMRP expression in mouse tumors has revealed FMRP to be a master regulator of immunosuppressive tumor microenvironments, such that its abrogation enables T cell inflammation and tumor immunity (1). Recent mechanistic insights will be presented.

A second goes beyond the immunosuppressive TME.  HPV16-induced cervical carcinomas evade the immune system by eliciting ‘systemic immunosuppression’, whereby tumors program an expansion of neutrophils in the bone marrow, spleen, and tumors that potently inhibit the development of tumor-antigen-specific T cells and obviate efficacy of a therapeutic vaccine (2). In ongoing unpublished studies, to be presented, we have elucidated this ‘action-at-a-distance’, involving ligands secreted from HPV16-expressing tumors acting on receptors expressed on myeloid progenitors in the lymphatic organs to induce immunosuppressive neutrophils, and developed a therapeutic strategy to abrogate it, enabling efficacy of a oncoprotein-based therapeutic vaccine.

(1)  Zeng et al. (2022). Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune         evasion. Science, PMID: 36395212.153.

(2)  Galliverti et al. (2020). Myeloid cells orchestrate systemic immunosuppression that impairs the efficacy of therapeutic vaccination and masks the effects of immunotherapy against HPV+ cancers. Cancer Immunology Research PMID: 31771984.