Decoding Rac mediated Cell Cannibalism, Immunodeficiency, and Supercharging Cancer Immunotherapy

How do these findings contribute to your research area?

CARs are like guides for immune cells (such as CAR-T for T cells), helping them spot and kill cancer by recognizing specific proteins. CAR-T cell immunotherapies have emerged as a groundbreaking approach for treating cancer; however, these therapies have limited success against solid tumors due to poor infiltration in the tumor microenvironment. Unlike T cells, CAR-M uses macrophages, adept at infiltrating solid tumors, that can devour and destroy tumors. Currently, one challenge for CAR-M is to increase whole cancer cell engulfment rather than cancer cell nibbling. Our study suggests that RaceCAR-M can effectively address this problem. 

Patients harboring RAC2E62K mutation suffering from T cell lymphopenia often encounter recurrent infections including pneumonia, bronchitis, and/or sinusitis due to compromised immune system. Currently, stem cell transplantation is the main therapy to address T-cell lymphopenia and its associated risks, which is expensive. Our work has provided the first evidence of mechanism of Rac2 mediated T cell lymphopenia that can help develop targeted therapies for these patients.

What was the exciting moment during your research?

Throughout our study, we experienced numerous “Aha moments!” In the ’90s, our lab discovered that expressing a hyperactive Rac1 protein in a few cells known as ‘border cells’ of a Drosophila egg chamber destroyed the entire tissue. Why did this happen? We did not know. This 25-year-old mystery was finally solved when evidence pointed to cannibalism. There is a step in normal Drosophila egg development where certain cells similar to the border cells engulf their neighbors because they are no longer needed. We thought that hyperactive Rac1 expression is prematurely hijacking this process via border cells. When I blocked a specific receptor involved in the late stage engulfment, it prevented the destruction of the egg chamber, confirming our suspicions. 

Our discovery coincided with a study on patients possessing a RAC2E62K mutation, hyperactivating RAC2, resulting in a severe T cell deficiency. The authors did not know the cause of this mysterious loss of T cells. We suspected that the lab’s recent revelation in fruit flies might shed light on this enigma. We wondered if the patients’ T cells were disappearing because their immune cells like macrophages with active Rac2 were eating them, much like the Drosophila border cells with active Rac were eating the egg chamber. I cultured human macrophage-like cells with and without hyperactive RAC2 together with T cells and observed that macrophages with hyperactive Rac engulfed more T cells, confirming our hypothesis. We then observed similar results when macrophages from the mice bearing RAC2E62K mutation were co-cultured with their own T-cells. However, T-cells with active Rac2 were also more vulnerable to engulfment from macrophage. So the most likely explanation for the patients’ T cell lymphopenia was a combination of increased engulfment by macrophages and increased vulnerability of the T cells themselves. Thus, our observations in fruit flies played a crucial role in unraveling a perplexing medical mystery in human patients.

Collaborating with Dr. Meghan Morrissey was icing on the cake. We demonstrated that these hyperactive RAC2E62K expressing macrophages, when engineered with a chimeric antigen receptor (CAR), were highly effective in eliminating entire cancer cells. Our fundamental observations in fruit flies not only solved a medical mystery but also paved the way for potential advancements in cancer immunotherapy. The journey from fruit fly tissue destruction to understanding immune system disorders and enhancing cancer treatment has been a truly satisfying scientific adventure.

What do you hope to do next?

I am currently assessing the efficacy of RacCAR-M in human monocyte derived macrophages. Later, I plan to test the effectiveness of RaceCAR-M against a variety of solid tumor targets in animal cancer models. We are also inviting biotech companies to partner with us in developing RaceCAR-M therapy. 

Where do you seek scientific inspiration from?

I draw scientific inspiration from many sources including my mentors. I enjoy participating in interdisciplinary scientific discussions, assimilating fresh ideas from diverse fields, connecting with scientists at meetings and conferences, and reflecting on how newfound insights can be applied to my research. My journey through this work has taught me how to address different aspects of a bigger problem using different models and come up with the holistic answer. I also derive inspiration and strongly advocate model organism based basic research because of the immense potential it holds in translational discoveries.

How do you intend to help Indian science improve?

India is poised for a transformative era in cancer immunotherapy. The first CAR-T therapy for treating relapsed-refractory B-cell lymphoma and leukemia has just been approved. This is the very beginning of India’s technical prowess in the cell therapy space. I am keen on expanding my network within the Indian research, medical and pharma community and sharing my knowledge, skills and expertise in CAR-M therapy. My vision involves a dual mission: educating the next generation of Indian researchers about the vast potential of cellular immunotherapies beyond cancer through platforms like biopatrika, and actively contributing to the very beginning of CAR-M research in India. I look forward to engaging with the Indian research, medical, and pharmaceutical sectors to spearhead CAR-M research in India in the near future.