Why do some ovarian cancer patients evolve better than others?

Dr. Subir Biswas’s interview with BioPatrika hosting “Vigyan Patrika”, a series of author interviews. Before joining H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA as a Postdoctoral fellow in the laboratory of Dr. José R. Conejo-Garcia in 2017, Dr. Biswas did his Ph.D. from the University of Calcutta under the mentorship of Dr. Arindam Bhattacharyya. Through his doctoral studies, Dr. Biswas contributed towards the understanding of breast cancer disease progression through the processes of epithelial-to-mesenchymal transition, migration, invasion and metastasis, and was able to underscore the role of mesenchymal stem cells in the polarization of immunosuppressive macrophages (The Journal of Immunology, 2019). Currently as a postdoctoral fellow, Dr. Biswas has been investigating several aspects of tumor immunology and immunotherapy. His principal project focusses on the development of a novel protocol for the ex vivo expansion and immortalization of tumor-infiltrating B lymphocytes and characterization of the nature and impact of antibodies produced at the tumor bed against tumor antigens. Here, Dr. Biswas discusses his paper titled “IgA transcytosis and antigen recognition govern ovarian cancer immunity” recently published in Nature (2021), where he demonstrated why some ovarian cancer patients evolve better than others and suggested possible approaches to improve patient outcomes.

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How would you explain your paper’s key results to the non-scientific community?

Ovarian cancer is one of the most severe cancer types among women with limited successful treatments available. In our recently published article, we have highlighted the immunotherapies that enhance anti-cancer immune responses are likely to show augmented therapeutic benefits against human ovarian cancer. The main take-home message is that a specific type of antibody (formally known as IgA) dominates the spontaneous antibody responses in ovarian cancer and such robust and prolonged anti-cancer responses predict better patient survival. These antibodies target multiple antigens expressed on the tumor cells’ membrane, or present in secreted molecules by the cancer cells. IgA antibodies exert both specific and non-specific anti-tumor activities, by redirecting specific cell types, such as myeloid cells against tumor cells causing cancer cell-killing, and internalization and passage through cancer cells, which express the receptor for these antibodies, known as polymeric immunoglobulin receptor (pIgR). Therefore, immunotherapies against ovarian cancer or other pIgR+ tumors using these antibodies might be more effective and a have better outcome.


Figure 1. Ovarian cancer tumor-derived IgA antibodies elicit protective immune responses through antigen-independent and antigen-dependent mechanisms.

we provided a basis for an innovative designing of immunotherapies that intend to synchronize T- and B-cell responses, unlike disregarding the humoral anti-tumor responses.

What are the possible consequences of these findings for your research area?

There are several clinical and bio-medical implications of these findings. We have provided a mechanistic foundation for an alternative usage of IgA-based antibodies, as opposed to the current exclusive usage of IgG-based antibodies, as novel immunotherapies. Additionally, we have provided novel approaches for characterizing the targets recognized by antibodies produced by tumor-associated B-cells. A substantial portion of these antigens are expressed on the cancer cell surface, and we are presently cloning reactive antibodies to customize them in Chimeric antigen receptor (CAR) T-cell immunotherapies, in addition to the direct immunotherapeutic targets. Further, in addition to the current T-cell-centric anti-cancer immunotherapies, we provided a basis for an innovative designing of immunotherapies that intend to synchronize T- and B-cell responses, unlike disregarding the humoral anti-tumor responses.

What was the exciting moment (eureka moment) during your research?

 The magnitude of the IgA-antibody response observed in ovarian cancer was the first exciting moment in the project. We were also surprised to discover that practically all ovarian tumors express the IgA (and IgM) receptor pIgR. We now believe that tumors of epithelial origin express pIgR. Further, for the first time we have discovered transcytosis of IgA antibodies through the pIgR+ ovarian cancer cells, which resulted in unpredicted consequences such as inhibiting cancer-promoting pathways and causing ovarian cancer cells sensitive to T lymphocytes-mediated killing.

What do you hope to do next?

Apart from determining whether these results can be generalized to other epithelial cancers, currently we are studying the activity and anti-tumor abilities of explicit tumor-derived antibodies, and we are looking forward to developing them in the form of novel immuno-therapeutics. We are also interested in examining the landscape and specificities of antibodies at tertiary lymphoid structures, which are special structures that mimic lymph nodes, and are present in ~20 percent of ovarian carcinomas and associated with improved outcome.

Where do you seek scientific inspiration?

I derive my scientific motivations from the excellent scientific environment and talented researchers present at the Moffitt Cancer Center. I am highly inspired by my postdoc mentor Dr. José R. Conejo-Garcia. He has always motivated me to think out-of-the box and encouraged me to perform cutting-edge experiments, which has helped me to become a better researcher. I was also involved in several collaborative projects in this lab and that has trained me to become an excellent team player. My initial inspiration towards hard-core cancer immunology came from my Ph.D. mentor Dr. Arindam Bhattacharyya, who provided me with the freedom to explore my research questions. Finally, I consider myself extremely lucky to be part of these excellent research groups during my Ph.D. and postdoctoral trainings.

How do you intend to help Indian science improve?

India’s science has significantly progressed over the last few decades, however, there has not been any comprehensive study done so far that has focused on tumor-associated B cells and its relevance to cancer progression in India, at least in my knowledge. I am happy that this field is progressing rapidly now and focusing more towards complete assessment of the anti-tumor immune responses, whereby multiple cell types of the immune system and other elements work in synchronization, rather than a narrow opinion of T lymphocytes as the only driver of immune burden against cancer progression. I am also optimistic that our published work and our upcoming papers will attract scientific groups working in the relevant field in India to study the immunobiology of solid cancers in a more holistic way. I am also very keen in utilizing my expertise and contributing towards the designing of novel immunotherapy approaches. If I ever get an opportunity to mentor young minds in India, I will try my best to motivate them towards pursuing research in tumor immunology.

Reference

Biswas, S., Mandal, G., Payne, K.K. et al. IgA transcytosis and antigen recognition govern ovarian cancer immunity. Nature 591, 464–470 (2021). https://www.nature.com/articles/s41586-020-03144-0

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Edited by: Neha Varshney

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