Biology subjects

de Carne Trecesson, S.

Publications and source records attributed to de Carne Trecesson, S..

6 recordsLinked to original sources

bioRxiv2025

Oncogenic RAS activity is linked to immune priming and adenosine-driven immune evasion in lung adenocarcinoma

Lung adenocarcinoma (LUAD) is a leading cause of cancer death worldwide, with RAS signalling as a key oncogenic driver. Although KRAS mutations have been linked to immune evasion in preclinical models, the relationship between RAS activity and tumour immunity or response to immunotherapy in patients remains unclear. Here, we applied our previously validated RAS84 transcriptional signature to stratify LUAD patient cohorts and dissect the immune landscape associated with RAS signalling. We report that tumours with elevated RAS activity exhibited features of immune priming, including increased immune infiltration, interferon response, and immune checkpoint gene expression, and showed improved progression-free survival in an independent cohort of patients treated with anti-PD-1. Yet, in both LUAD tumours and cell lines, RAS activity also correlated with elevated immunosuppressive interstitial adenosine mediated by transcriptional regulation of several components of the adenosinergic pathway. In orthotopic pre-clinical models of high-RAS activity lung tumours, blocking adenosine signalling delayed tumour growth and improved response to anti-PD-1 and KRAS inhibition, with a significant effect on innate immunity. This study reveals a dual role for RAS signalling in tumour progression, fostering a pro-immunogenic environment whilst simultaneously dampening anti-tumoural immunity via mechanisms including extracellular adenosine accumulation. Stratifying patients based on RAS transcriptional activity, rather than genetic alterations alone, could inform immunotherapy strategies and improve clinical outcomes.

cancer biology↗

bioRxiv2025

Leveraging death of drug-sensitive cancer cells to promote immune-mediated bystander killing of subclones of drug-resistant tumor cells

The response of lung cancer patients to drugs targeting the G12C mutant form of KRAS is limited by the development of resistance through multiple mechanisms. In order to achieve lasting benefit with these therapies, effective strategies for tackling the evolution of drug resistance are required. We have developed a preclinical model system to mimic the development of resistance to KRAS G12Ci inhibitors (G12Ci) such as adagrasib and RMC-4998. Treatment of tumours containing a minor subpopulation of resistant cancer cells with G12Ci leads to their rapid outgrowth to replace the drug-sensitive cells within a few weeks. However, when combined with therapies that, at least in part, target the immune response, such as SHP2 inhibitors or PD-1 blockade, drug-resistant cells can be eliminated, even by drug combinations that do not impact their growth in the absence of drug-sensitive cells. This bystander killing of drug-resistant cells when drug-sensitive cells are targeted is dependent on an intact adaptive immune system. Mechanistically, these combination therapies lead to profound remodelling of the tumour immune microenvironment, with influx of T cells recognising a tumour associated antigen shared between drug-resistant and drug-sensitive cancer cells. Promotion of immune-mediated bystander killing of drug-resistant cells may provide a paradigm for tackling the problem of drug resistance in cancer more broadly.

cancer biology↗

bioRxiv2024

Combining RASG12C(ON) inhibitor with SHP2 inhibition sensitises immune excluded lung tumours to immune checkpoint blockade: a strategy for turning cold tumours hot

Mutant selective drugs targeting the inactive, GDP-bound form of KRASG12C have been approved for use in lung cancer, but responses are short-lived due to rapid development of resistance. In this study we use a novel covalent tri-complex inhibitor, RMC-4998, that targets RASG12C in its active, GTP-bound form to investigate treatment of KRAS mutant lung cancer in various immune competent mouse models. While this RASG12C(ON) inhibitor was more potent than the KRASG12C(OFF) inhibitor adagrasib, rapid pathway reactivation was still observed. This could be delayed using combined treatment with a SHP2 inhibitor, RMC-4550, which not only impacted RAS pathway signalling within the tumour cells but also remodelled the tumour microenvironment (TME) to be less immunosuppressive and promoted interferon responses. In an inflamed, "hot", mouse model of lung cancer, RASG12C(ON) and SHP2 inhibitors in combination drive durable responses by suppressing tumour relapse and inducing development of immune memory, which can also be induced by combination of RASG12C(ON) and PD-1 inhibitors. In contrast, in an immune excluded, "cold", mouse model of lung cancer, combined RASG12C(ON) and SHP2 inhibition does not cause durable responses, but does sensitise tumours to immune checkpoint blockade, enabling efficient tumour rejection, accompanied by significant TME reorganization, including depletion of immunosuppressive innate immune cells and recruitment and activation of T and NK cells. These preclinical results demonstrate the potential of the combination of RASG12C(ON) inhibitors with SHP2 inhibitors to sensitize anti-PD-1 refractory tumours to immune checkpoint blockade by stimulating anti-tumour immunity as well as by targeting KRAS-driven proliferation in tumour cells.

cancer biology↗

bioRxiv2023

In vivo CRISPR screen identifies KRAS-induced COX-2 as a driver of immune evasion and immunotherapy resistance in lung cancer

Oncogenic KRAS impairs anti-tumour immune responses, but effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identifies mechanisms by which oncogenic KRAS promotes immune evasion, most notably expression of immunosuppressive cyclooxygenase-2 (COX-2) in cancer cells. Oncogenic KRAS was a potent inducer of COX-2 in both mouse and human lung cancer which was suppressed using KRAS inhibitors. COX-2 acting via prostaglandin E2 (PGE2) promotes resistance to immune checkpoint blockade (ICB) in both mouse and human lung adenocarcinoma. Targeting COX-2/PGE2 remodelled the tumour microenvironment by inducing pro-inflammatory polarisation of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX-2 expression contributed to tumour relapse after prolonged KRAS inhibition. We propose testing COX-2/PGE2 pathway inhibitors in combination with KRAS G12C inhibition or ICB in patients with KRAS-mutant lung cancer.

cancer biology↗

bioRxiv2021

Oncogenic RAS activity predicts response to chemotherapy and outcome in lung adenocarcinoma

Activating mutations in the driver oncogene KRAS occur in 32% of lung adenocarcinomas, leading to more aggressive disease and resistance to therapy in preclinical studies. However, the association between KRAS mutational status and patient outcome or response to treatment remains unclear, likely due to additional events modulating RAS pathways. To obtain a broader measure of RAS pathway activation beyond KRAS mutation only, we developed RAS84, a transcriptional signature optimised to capture RAS oncogenic activity in lung adenocarcinoma. Using RAS84 to classify lung cell lines, we show that RAS transcriptional activity outperforms KRAS mutation to predict resistance to chemotherapy drugs in vitro. We report that 84% of lung adenocarcinomas show clear transcriptional evidence of RAS oncogenic activation, falling into four groups characterised by coincident mutation of STK11/LKB1, TP53 or CDKN2A. Given that 65% of these RAS pathway active tumours do not have KRAS mutations, we find that the classifications developed when considering only KRAS mutant tumours have significance in a much broader cohort of patients. Critically, patients in the highest RAS activity groups show adverse clinical outcome and reduced response to chemotherapy. The stratification of patients using gene expression patterns linked to oncogenic RAS signalling activity instead of genetic alterations in cancer genes could ultimately help clinical decision making.

cancer biology↗

bioRxiv2020

APOBEC3B expression generates an immunogenic model of Kras mutant lung cancer

Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumour regression but ultimately fail to cure these cancers, leading to intense interest in how best to combine them with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumours with the host immune system are inadequate, in part due to the low tumour mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumour mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumour mutational burden and autochthonous tumours remained refractory to immunotherapy. However, by establishing clonal cell lines from these tumours we generated an immunogenic syngeneic transplantation model of KRAS mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, we found that anti-tumour immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C-expressing versions of these tumours was markedly potentiated by the adaptive immune system, providing a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.

cancer biology↗