Deciphering the molecular and functional heterogeneity of group 2 innate lymphoid cells in cancer.

Cancer, with its intricate etiology and progression, continues to pose significant challenges to the medical community. At its core, this disease is not just about uncontrolled cellular growth, but also about how these malignant cells interact with their environment, especially the components of the immune system. Over the years, as our comprehension of cancer has evolved, so has our realization of how integral the immune system is in modulating cancer progression. Sometimes the immune system recognizes and efficiently combats the malignancy, leading to tumor eradication. At other times, cancer cells can evade or even suppress immune responses, paving the way for tumor growth and metastasis. The sheer complexity of these interactions can vary across cancer types and stages, and even among individuals with the same type of cancer. Emerging from these insights is the promising realm of immunotherapy. By leveraging our growing knowledge of how immune cells recognize and respond to cancer cells, we can design treatments that boost the body's natural defenses against tumors. Instead of a one-size-fits-all approach, therapies can be tailored based on the individual's unique immune landscape and the specific interactions occurring between their immune cells and cancer cells. Our research centers on a recently recognized member of the family of innate lymphoid cells (ILCs): group 2 innate lymphoid cells (ILC2s). Despite the absence of antigen receptor expression, they parallel adaptive helper T (Th) cells due to comparable expression of transcription factors, production of cytokines, and functional attributes. ILC2s, characterized by expression of GATA-3 transcription factor and production of copious amounts of type 2 cytokines upon exposure to stimuli like IL-33 and IL-25, are often seen as the innate parallel to Th2 cells. While ILC2s predominantly act as frontline defenders against parasitic invasions that elicit type 2 immune reactions, they also appear to influence tumorigenic pathways. The specific relationship between ILC2s and tumor cells remains ambiguous, with data pointing to both pro-tumor and anti-tumor roles. Our data suggests that this dual character might be rooted in ILC2s' molecular diversity. In studies utilizing the B16F10 mouse melanoma, we discerned a unique molecular pattern in ILC2s linked to their anti-tumor properties. Melanomas undergoing growth inhibition in IL-33 treated mice displayed an increase in the number of ILC2s bearing this particular pattern. Notably, this same pattern has a positive association with extended survival rates in melanoma-affected humans. At the same time melanoma cells quench the tumoricidal activity of ILC2s by modulating the tumor microenvironment. In summary, our discoveries underscore the potential of ILC2s in combating melanoma. Yet, melanomas seem to wield multiple tactics to counteract ILC2s' anti-tumor abilities. We postulate that by focusing on this specific molecular pattern and neutralizing the hostile microenvironment imposed by malignant cells we could amplify their anti-melanoma efficacy and pave the way for innovative treatments that are both more effective and potentially less toxic than conventional cancer therapies.

The outcomes of this project are significant in the realm of oncology and immunology. Foremost, the discovery of a distinct population of ILC2s connected with anti-tumor attributes represents a significant leap in our comprehension of ILC2 subsets and their interplay with malignant cells. This novel population, distinguished by its unique profile, has the potential to reshape therapeutic paradigms. With its inherent tumor-fighting characteristics, this ILC2 subset could pave the way for the development of innovative therapies that harness the body's own immune responses to combat malignancies, perhaps even providing a template to analyze such properties not only in melanoma but also in other tumor types. Furthermore, our introduction of the 3D skin melanoma spheroid-based model stands as a testament to the ingenuity of this research initiative. Traditional 2D models have had their limitations, often providing a more superficial understanding of cell-to-cell interactions. In contrast, our 3D spheroid model offers a more physiologically relevant environment, allowing for intricate cellular interactions to be observed in a manner reminiscent of actual tumor microenvironments. This innovative tool serves to bridge the gap between in vitro studies and in vivo realities. By using this model, we can gain invaluable insights into the dynamics of immune and cancer cell interactions, potentially unlocking novel intervention points for therapeutic targeting. In essence, the dual achievements of this project - both the identification of the unique ILC2 population and the development of the 3D spheroid model - underscore the project's transformative impact on cancer research. As we delve deeper into these discoveries, we stand at the precipice of potential advancements that could revolutionize how we understand, and more importantly, how we approach cancer therapeutically.

Cancer is associated with a heavy burden on society in terms of health and economic costs. Although great advances have occurred in the field of cancer immunotherapy, the benefit, to date, has been limited to a minority of patients with certain cancer types. In addition, as a result of more successful immunotherapy treatments, a significant subset of patients who initially respond but eventually relapse emerged. Group 2 innate lymphoid cells (ILC2s) represent the most recently identified member of the innate lymphoid cell (ILC) family. Their role in cancer seems contradictory, as they have been associated with tumor-suppressing as well as tumor-promoting activities. Therefore, the possibility to enhance and/or reorientate their tumor-suppressing and/or tumor-promoting activities, respectively, provides an attractive strategy in the field of cancer immunotherapy. This therapeutic strategy requires, however, a better understanding of the role and the mechanisms that regulate the function of ILC2s in different tumor sites, when facing complex interactions with the cellular and molecular components of the tumor microenvironment. Our preliminary data and the literature strongly support the hypothesis that the immune microenvironment is highly variable between different tumors or even areas of the same tumor. In addition, recent evidence indicates that metabolic pathways within the tumor microenvironment shape the diversity of infiltrating immune cells. Therefore, the current proposal aims to characterize ILC2s in different tumor areas and their contribution to the tumor growth as well as to assess the impact of tumor-derived lactic acid on the function of intratumoral ILC2s. A broader understanding of the relevance of ILC2s in cancer is essential towards the design of safe and successful therapeutic strategies.