美国弗朗西斯克里克研究所2024年招聘博士后（肿瘤免疫学）

弗朗西斯·克里克研究所（Francis Crick Institute）：2010年诺贝尔奖得主、遗传学家保罗·纳斯提议将英国伦敦两家最大的生物医学研究中心（英国国家医学研究所，英国癌症研究中心）合并在一起，建立一个巨型实验室。

2015年11月实验室将竣工，2021年，这家耗费6.5亿英镑（约63亿人民币）、占地9.3万平方米的研究所将全功率运行，将有1600位科学家和工作人员在这里工作，它将成为欧洲最大的单一生物医学实验室。

Postdoctoral Fellow

The Francis Crick Institute

Application Deadline Deadline:

31 July 2024Job Salary £43,210

Contact term:

• This is a full-time fixed term position for 4 years on Crick Terms & Conditions of employment

The Research Group

Julian Downward’s laboratory (Oncogene Biology) investigates the mechanisms by which mutant oncogenes drive the formation of tumours and how understanding this better can promote more effective approaches to treating cancer in the clinic. We particularly focus on the RAS family of oncogenes, which are the most frequently mutated oncogenic drivers in human cancer. We are seeking a talented and motivated postdoctoral research fellow with experience in tumour immunology to join our group.

The first generation of clinical KRAS inhibitors, G12C selective sotorasib and adagrasib, are seriously compromised by the rapid development of drug resistance in clinical use for lung cancer. We hypothesise that the killing of drug sensitive tumor cells could promote an immune response against drug resistant subclones that share similar antigens. We have adapted our mouse lung cancer models described above to study this potential bystander killing, utilizing mixed populations of drug sensitive G12C KRAS mutant lung cancer cells with otherwise isogenic G12D KRAS drug resistant cells, or non-engineered drug resistant populations that have arisen under selective pressure in vivo. The cell populations are tagged and barcoded. They will be used to address the following issues:

• What constrains immune-mediated bystander killing of G12C inhibitor drug resistant tumor cells? We will use multiplexed imaging and spatial transcriptomics to identify responses to G12C inhibitor in drug sensitive tumor cells, in drug resistant tumor cells and in non-tumor cells of the tumor microenvironment. Preliminary data from more narrow interrogation of the tumor response using imaging mass cytometry, or single cell RNA-Seq lacking spatial component, suggest a number of candidate immunosuppressive mechanisms, including regulatory T cells, extracellular adenosine signaling, TGFb and CD47/SIRPa.

• Would rational combination of G12C inhibitor with immune therapies targeting the pathways implicated by the above work provide improved response of the drug resistant tumor cell subpopulation, as well as the drug sensitive bulk population?

• How would these combinations compare with standard immune checkpoint blockade combinations such as those involving PD1 or CTLA4 blockade, and also SHP2 inhibition, a therapy acting in part on cells of the tumor immune microenvironment, particularly immunosuppressive myeloid cells?

• Once optimal combination strategies have been identified to eliminate drug resistant subpopulations, what would be the limits of the bystander killing effect in terms of drug resistant cell fraction and overall tumor size? Does treatment sequencing impact the effectiveness of the combination? In mice that have rejected tumors, is immune memory established and for how long?

• Findings from the mouse models will be compared to publicly available datasets from human lung cancer to verify, or otherwise, the presence of immune suppressive features in the tumor microenvironment that would indicate the potential for similar responses in human tumors. Beyond the scope of the proposed project, these would form the basis for clinical trials of selected combinations, initially in a neo-adjuvant setting with analysis of the immune response in drug treated tissue samples.

We hope that this work will allow the identification of therapeutic approaches to reverse the shielding of the KRAS mutant lung tumours from the immune system and how best to eliminate the acquisition of drug resistance by minor cell populations in advanced tumours to enable effective long-term treatment and ultimately cure of this disease.

Information about the work of the laboratory can be found at the links below:

http://crick.ac.uk/research/a-z-researchers/researchers-d-j/julian-downward/

http://scholar.google.co.uk/citations?user=9bDwgogAAAAJ&hl=en

https://orcid.org/0000-0002-2331-4729

Key experience and competencies

Qualifications, experience and competencies

• PhD in relevant subject area or in the final stages of PhD submission

• Good knowledge and experience in cancer biology, molecular cell biology and immunology

• Technical expertise in tumour immunology, such as immune phenotyping by FACS, single cell sequencing, multiplexed spatial imaging or mass cytometry

• Experience in the use of mouse models in cancer or immunology research

• Experience in the use of bioinformatics to analyse large biological datasets

• Track record of writing papers as evidenced by publications or submitted manuscripts in refereed journals

• Evidence of data presentation at scientific meetings

• Ability to work with minimal supervision using own initiative to organise and prioritise own work

• Ability to define and solve research questions

• Pro-active in innovation and problem solving

• Experience of experimental design

Postdoctoral Fellows are expected to lead their own projects, contribute to other projects on a collaborative basis (both in the lab and with external collaborators) and guide PhD students in their research. The ability to work in a team is essential.