Interview with a Scientist: "Immune resistance in lung cancer" Dr. Marzio, NY, USA

Author: Laura Pozzi Ph.D., Scientific Content Manager, Atlas Antibodies AB, Sweden

Non-small cell lung cancers (NSCLCs) are epithelial lung cancers that differ from small cell lung cancers (SCLCs) by cell morphology and histology. Almost 85% of lung cancers are NSCLCs. 

Examples of NSCLCs include adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Still, several other types occur less frequently, and all varieties can occur in unusual histologic variants.  

Although NSCLCs are less aggressive and progress more slowly than SCLCs, they are often identified later, and by the time of diagnosis, they will have already spread beyond the lungs.  

Moreover, NSCLCs (in particular NSCLCs harboring KEAP1 mutations) are less sensitive and often resistant to chemotherapy, radiation, and immune checkpoint inhibitors immunotherapy compared with SCLCs. 

Which mechanisms drive immune-resistant responses in patients with NSCLCs? 

In a recently published paper,” EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion” (Marzio et al. Cell, 2022) the authors show that KEAP1 targets the transcriptional repressor EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair and anti-tumor immunity. 

We asked Dr. Marzio from the New York University Grossman School of Medicine to explain how KEAP1 and EMSY-mediated mechanisms promote immune evasion and drive immune-resistant responses in patients with NSCLCs. 

Q1: Tell us a bit more about your overall research goals. What is the fascinating aspect of it? 

Dr. Marzio: The proteome of a cell determines its phenotypes and is predominantly regulated by the ubiquitin-proteasome system (UPS). We study a large family of E3 ubiquitin ligases (E3s) known as cullin-RING ligases (CRLs), which ubiquitylate numerous substrates via variable/exchangeable substrate receptors.  

Over the last 25 years, we have established paradigms for understanding how CRLs recognize specific substrates at the molecular level and elucidated how signaling cascades couple this recognition to the regulation of cellular physiology. Importantly, we investigate how dysregulation of these newly described molecular mechanisms contributes to malignant transformation. 

Q2: What question were you setting out to address when you started this work?   

Dr. Marzio: Among the major genetic lung cancer drivers, the E3 KEAP1 (kelch-like ECH associated protein 1) is mutated in ~20% of non-small cell lung cancer (NSCLC) patients and is the third most frequently mutated gene in lung adenocarcinomas.  

KEAP1-mutant NSCLCs are characterized by a high tumor mutational burden (TMB), which is a measurement of the number of mutations carried by tumor cells. A high TMB typically correlates with the induction of an anti-tumor immune response. However, patient data reveals that KEAP1-mutated NSCLCs display immune-evasive features such as reduced immune infiltration and resistance to current immunotherapy. 

” Our research shows that deregulation of the ubiquitin-proteasome system promotes suppression of innate immunity, which fosters lung cancer immune evasion”. 

Q3: Why is this important? 

Dr. Marzio: To date, despite the growing interest in the role of the UPS in regulating immune responses, there has been rather limited progress in understanding how the deregulation of E3 ubiquitin ligases (E3s) participate in anti-tumor immunity.  

Our research has provided evidence that deregulation of the UPS promotes suppression of innate immunity, which in turn fosters lung cancer immune evasion.  

The ultimate goal of these efforts has been to understand the underlying molecular drivers of tumorigenesis to leverage these genetic and biochemical alterations for therapeutic applications.

Q4: What were the key findings that came out of the work? 

Dr. Marzio: Since the concept of synthetic lethality of PARP inhibitors (PARPis) in BRCA1/2 mutated tumors was first described, several other ‘BRCAness’ genes have been identified that mimic this phenotype. The definition of ‘BRCAness’ is a gene that, when mutated, lost, or overexpressed, induces a defect in homologous recombination repair (HRR) and subsequent sensitivity to PARP inhibition.  

We have recently identified the tumor suppressor KEAP1 as a novel BRCAness gene. Specifically, we identified and characterized a molecular mechanism by which mutations in KEAP1 induce stabilization of the transcriptional repressor and BRCA2 inhibitor EMSY, which subsequently promotes genomic instability and immune evasion.  

Notably, our findings provide a mechanistic basis for how EMSY negatively regulates the type I interferon response, leading to the suppression of innate immunity, thereby promoting immune evasion in KEAP1-null tumors. Moreover, our data suggest that targeting the PARP and STING pathways, individually or in combination, represents a novel therapeutic strategy in NSCLC patients harboring alterations in KEAP1. 

Q5: What are the future directions for the work?

Dr. Marzio: By controlling protein abundance and activity, the UPS serves as a key regulator of a plethora of cellular mechanisms, including immunological homeostasis.  

To date, despite our extensive knowledge regarding the role of the UPS in regulating key cellular events (e.g., cell cycle, cell proliferation, etc.), there has been limited progress in understanding how deregulation of E3s participates in anti-tumor immunity.  

Therefore, our future goals are to characterize novel components of the UPS machinery in immunosurveillance. 

Thank you, Dr. Marzio, for sharing your science with us!

Marzio A, Kurz E, Sahni JM, Di Feo G, Puccini J, Jiang S, Hirsch CA, Arbini AA, Wu WL, Pass HI, Bar-Sagi D, Papagiannakopoulos T, Pagano M. EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion. Cell. 2022 Jan 6;185(1):169-183.e19.

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