Restoring antitumor immunity with dendritic cell reprogramming strategies: a PhD Interview with Alexandra Gabriela Barros Ferreira
Alexandra Gabriela Barros Ferreira, a Ph.D. student at Lund University, is set to defend her thesis on Friday, 17 November 2023. Alexandra’s pursuit of scientific discovery has led her to focus on developing innovative strategies to combat cancer. Her research involves direct reprogramming approaches, which function like a Trojan horse, enabling cancer cells to be targeted by the immune system.
In this interview, Gabriela shares her favorite discoveries, the highlights of her Ph.D. journey, and her aspirations to transition into industry.
What have your Ph.D. studies focused on?
"For the past two decades, immunotherapy revolutionized cancer treatment. However, responses vary significantly among eligible patients. Immunotherapy can fail in patients with cancer when certain cancer cells can hide from the immune system. By using direct reprogramming strategies, I could induce the expression of tumor antigens on the surface of cancer cells, making them visible to the immune system again.
My Ph.D. studies have focused on restoring anti-tumor immunity with dendritic cell reprogramming strategies. We focused particularly on harnessing reprogramming, or direct cellular reprogramming, to induce antigen presentation in cancer cells. In 2018, our research group identified the three transcription factors that allow us to convert fibroblasts, for example from the skin, into type 1 conventional dendritic cells (cDC1). cDC1 are professional antigen-presenting cells; when it comes to cancer they are critical as they present tumor antigens to the killer cells of the immune system and orchestrate the anti-tumor immune response. However, cDC1 can be compromised in cancer patients and some cancer cells lack these antigen-presenting proteins on their surface, impacting immunotherapy response. Direct reprogramming strategies with cDC1-specific factors can induce antigen-presentation in cancer cells, making cancer cells visible to the immune system and easier to fight.
In our latest publication, we showed that overexpression of cDC1-specific factors induce a cDC1-like phenotype in reprogrammed cancer cells and endow them with antigen presentation abilities in vitro. More importantly, we showed that the treatment of tumor-bearing mice with reprogrammed cancer cells increases survival and controls tumor growth by potentiating anti-tumor immune responses. When we combined reprogrammed cancer cells with immune checkpoint immunotherapy, the tumors regressed in some mice showing a synergistic effect between the two. So, we hope this will progress to a gene therapy that can target the tumor microenvironment, turning cancer cells into antigen-presenting cells and killing cancer from the inside like a Trojan horse,” explains Gabriela.
Can you tell us about the cover of your thesis?
“For my cover, I wanted to convey the idea of reprogramming as a metamorphosis of an adult cell becoming a different cell type. Based on this vision of a cancer cell becoming a dendritic cell, I used the Microsoft Bing image creator powered by DALL-E 3. These results inspired me to draw the final cover of my thesis. I didn't want to use the exact images as they were not exactly what I wanted, but they helped to bring what I had in mind to life.
Using Illustrator, I drew the cover myself based on these generated images. Then a friend helped me to paint the drawing using a watercolor style, which reflects me in a way. The pinks and the greens and all the multi-colored aspects, that was the idea I had from the beginning - a watercolor splash of a cell becoming another,” describes Gabriela.
How did you end up doing a Ph.D. at Lund Stem Cell Center?
“I'm from the north of Portugal, a city named Braga, near a nature reserve with all kinds of beautiful greenery. I always liked science and that's how I ended up in the biomedical sciences. I wanted to do something related to biomedicine, something related to therapies. During my bachelor's, I found that I liked immunology and genetics and that's how I ended up in the reprogramming field. With reprogramming, I could combine both fields, and develop immune cell reprogramming as a therapy for cancer.
All my studies were based in different cities in Portugal, my bachelor's, and my master's. For my master's, I was at Coimbra University where I worked with Professor Filipe Pereira. After I finished my master thesis, he announced he would be moving to Lund University. At the time, I had already applied for a scholarship to do my Ph.D. in his lab. I was awarded the grant, so I then had to choose between staying in Portugal and doing my Ph.D. at a distance or embracing the opportunity to come here to Lund.
I think that was the easiest choice I had to make during the PhD. I’ve enjoyed my time here in Lund. Despite the cold, I have even enjoyed the weather, especially the summers here. I like the culture, I love the architecture, and the clean air. I love the cozy, familiar feeling that Lund has as a small city while still being very close to bigger cities nearby like Malmö and Copenhagen,” expresses Gabriela.
What have you found the most enjoyable during your Ph.D. studies?
“Overall, my time as a Ph.D. student has been great. I’ve made wonderful friends during the Ph.D.; within our research group and outside of it. I’ve formed good scientific connections as well. This is also important to highlight, the network we form from the connections made during the Ph.D., be it colleagues or other PIs, other students and researchers.
But I think the most enjoyable aspect of the Ph.D. has been the constant learning of new things and being in constant contact with new techniques. Especially in the beginning, in the first three years of my Ph.D., it was all about learning as much as I could. I’ve also found the excitement around my own results, and even more so, other people’s achievements and scientific discoveries throughout these years to be very enjoyable. This is why I love science; I love the constant learning aspect of it all.
One of the aspects I’m most proud of was creating a way to assess if T-cells could target reprogrammed cancer cells for elimination. For this, I had to mix two different protocols, one based on microscopy and another on flow cytometry. I combined these two to make a flow cytometry assessment evaluation of T-cell mediated killing of reprogrammed cancer cells. It was a small part of a larger project, but it took a lot of reading, and a lot of understanding, to determine what the right controls would be, and what conditions were needed. In the grand scheme, it was a small achievement, but one that I feel like answered a lot of questions,” highlights Gabriela.
What has been the most challenging aspect?
“The most challenging has probably been related to prioritizing and preserving mental health in general. The Ph.D. is made of ups and downs, and as humans, our brains tend to cling to the negatives. So, it was difficult to overcome that at times. I think once I learned how to prioritize my mental health, everything went smoother. Also learning to be thankful and happy for all the small achievements, was enough to keep motivation going to feel like I would reach the final goal. I think that was important to learn,” says Gabriela.
What are your plans following your Ph.D. defense?
“There is nothing mapped out just yet. For now, I know that Lund and Sweden will be home for a while longer, I’ve started to make roots during the past few years here. I do know that I want to go into industry, but I'm not closing the door to academia. There is a reason why I began this journey, and it was the feeling of freedom, of always learning something new for yourself, and for your goals that come with the academic world. But I want to have other experiences and other challenges, so I’m still looking to find what will fit me best for the next chapter of my adventure,” answers Gabriela.
Any tips or advice for future Ph.D. students?
“My advice is something I wish I would have practiced from the beginning. To anyone who's starting their Ph.D., I think the most important thing is to have an organizational method from the beginning. For me, it meant deciding how I wanted to acquire data and how to analyze it. In the first two years, I think it took me longer to get this going. That's why I regret a lot of my non-organizational skills in the beginning.
So, to start strong, I recommend having an organization method that involves knowing well how to acquire, analyze, and keep the data. Make sure you keep everything very tidy, safe, secured, and backed up so you don't have to scramble looking through four years of disorganized work to redo it again. That is the most important thing I noticed when I look back. I only started having a method that worked for me in the middle of my Ph.D. and for that, I'm super grateful because it became easier to look back and remember what I did before. Reaching that point, though, where I had to go back several times during the Ph.D. to redo things was not easy nor was it fun to do,” concludes Gabriela.
Alexandra Gabriela Barros Ferreira
Cell Reprogramming in Hematopoiesis and Immunity
Department of Laboratory Medicine
Email: Alexandra_Gabriela [dot] Ferreira [at] med [dot] lu [dot] se (Alexandra_Gabriela[dot]Ferreira[at]med[dot]lu[dot]se)
Department of Laboratory Medicine
Email: Filipe [dot] Pereira [at] med [dot] lu [dot] se (Filipe[dot]Pereira[at]med[dot]lu[dot]se)
Ph.D. Defence Details:
Alexandra Gabriela Barros Ferreira defends her Ph.D. thesis “Restoring antitumor immunity with dendritic cell reprogramming strategies” on Friday, November 17th at 14:30 in Segerfalksalen BMC A10, Sölvegatan 17, Lund.
- The opponent is Dr Konrad Hochedlinger, Harvard
- The chairman of the dissertation is Professor Jonas Larsson
To find out more about the event and save the date please visit our calendar.
Read the full Ph.D. thesis in the Lund University Research Portal.