Periodic Reporting for period 1 - MacrophInt (Targeting integrin signaling in tumour-associated macrophages to combat cancer progression and resistance)
Periodo di rendicontazione: 2019-11-01 al 2021-10-31
Macrophages are innate immune cells that are present in all tissues of the body to maintain tissue homeostasis and immune surveillance. In several pathological conditions, including infection, injury, and inflammation, macrophages derived from blood monocytes are recruited to tissues and either participate in disease resolution and tissue repair or aid in progression of disease as in chronic inflammation. Macrophages are also massively recruited in the majority of solid tumours. The poor prognosis is largely correlated with the infiltration of tumour-associated macrophages. They promote tumour progression and interfere with the effectiveness of various anti-cancer therapies. Unsurprisingly, therapies that aim to either deplete or reprogram macrophages deserve considerable attention. However, care should be taken when modulating immune responses so as not to interfere with essential macrophage functions. Remarkably, all immune cells use amoeboid migration, and macrophages are able to use the mesenchymal mode of migration in dense tissues and most tumours. Unlike the amoeboid mode, mesenchymal migration requires podosomes which are specialized cellular structures involved in integrin-mediated cell adhesion. This feature deserves attention in order to specifically limit the recruitment of macrophages into tumours to neutralize their roles in disease progression, while preserving healthy macrophage functions. Integrin adhesion receptors are proven therapeutic targets in many diseases; however, complete blockage of their function often leads to mechanism-based toxicity limiting the use of integrin antagonists. The Macrophint project aimed to target the intracellular signaling pathways that orchestrate the integrin-dependent mesenchymal migration of macrophages. This strategy aligns with the emerging paradigm that signaling events in blood cells operate in both a cell-type and integrin-specific manner, providing unique pathways to manipulate immune cell recruitment into specific tissues. The Macrophint research program devised novel and unanticipated avenues to block mesenchymal macrophage migration and tumour infiltration to synergize with combination therapies that simultaneously target pro-tumour stromal cells and cancer cells. In addition, the individual Marie Sklodowska Curie Actions fellowship was also intended to promote the career of the beneficiary researcher and to contribute to raising public awareness of the research work carried out.
The Macrophint research program was structured around several workpackages with scientific goals, training objectives for the researcher in charge of the project, career development, and dissemination of the findings to the general public and the scientific community. On a scientifical level, the project contributed to determining the role of integrin regulatory pathways in the mesenchymal migration of macrophages without any impact on their amoeboid migration. Additionally, blocking the function of integrins in macrophages has also been shown to lead to a significant reduction in tumour growth. In addition, the migratory properties of macrophages are influenced depending on their state of differentiation. The project also identified key molecules in the regulation of integrins during the mesenchymal migration of macrophages and their infiltration into tumours. It has also contributed to improving our understanding of the regulation and function of integrins in podosomes, which are cellular structures involved in the migration of macrophages in dense environment, comparable to those encountered in solid tumours. With regard to the development of the career of the researcher, the project has made it possible to shed light on new research paths that will ensure the scientific independence of the fellow. The latter also acquired certifications and technical and theoretical skills thanks to the training he carried out for the research program. The scientific, administrative and budgetary management of the project was ensured by the fellow. At the same time, the scholarship holder supervised a doctoral student and three master's students. Taken as a whole, the Macrophint project enabled the fellow to increase his visibility in the scientific field and in particular enabled him to develop new scientific collaborations at the local and national levels and also to increase his competitiveness to obtain new funding for his career. The fellow obtained a permanent position as a research scientist at the National Center for Scientific Research (CNRS) in France and was then able to create his own research group to pursue an independent career. In terms of knowledge transfer, the researcher has already published a scientific paper related to the Macrophint project. In addition, the data generated will contribute to the publication of at least two other articles in peer-reviewed journals with open access policy in the months or years to come. Finally, despite the pandemic linked to Covid-19 which was a hindrance to exchanges and public meetings, the researcher took part in several conferences to disclose the results obtained to his peers. In addition, he organized a day of seminars on the topic of the tumour microenvironment to encourage new collaborations at the local level. He has also participated in public awareness actions through radio appearances, charity events and articles in the regional press. In conclusion, the project achieved most of its objectives for the period, with relatively minor deviations.
Cancer is the second leading cause of death and morbidity worldwide. While several approaches are being developed to combat cancerous diseases, macrophage-focused therapies are entering the clinical arena. The principle is that macrophage-directed therapies are best used to complement conventional cytoreductive therapies, angiogenesis inhibitors and immunotherapy. The clinical applicability and efficacy of macrophage-targeted therapies requires a better understanding of the unique characteristics of tumour-associated macrophages to support their infiltration into tumours. Completion of the Macrophint project has identified novel molecular targets to effectively inhibit macrophage recruitment into dense tissues, including solid tumours, with the potential to preserve other macrophage functions. Specifically, the research program provided a conceptual understanding of the regulatory mechanisms that act on the integrin-dependent migration of macrophages. Second, it established the potential of targeting integrins as a novel pathway to inhibit macrophage tissue infiltration in tumours while maintaining macrophage-mediated host defence. Future results may reveal new points of intervention to specifically manipulate macrophage tissue infiltration. Additionally, macrophage tissue infiltration also occurs in many other disease settings and there is potential for identifying targets of interest for the management of infectious and inflammatory diseases, which are increasingly growing diseases in western countries.