CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours.

Chimeric antigen receptor (CAR) therapy has had a transformative effect on the treatment of haematologic malignancies1-6, but it has shown limited efficacy against solid tumours. Solid tumours may have cell-intrinsic resistance mechanisms to CAR T cell cytotoxicity. Here, to systematically identify potential resistance pathways in an unbiased manner, we conducted a genome-wide CRISPR knockout screen in glioblastoma, a disease in which CAR T cells have had limited efficacy7,8. We found that the loss of genes in the interferon-γ receptor (IFNγR) signalling pathway (IFNGR1, JAK1 or JAK2) rendered glioblastoma and other solid tumours more resistant to killing by CAR T cells both in vitro and in vivo. However, loss of this pathway did not render leukaemia or lymphoma cell lines insensitive to CAR T cells. Using transcriptional profiling, we determined that glioblastoma cells lacking IFNγR1 had lower upregulation of cell-adhesion pathways after exposure to CAR T cells. We found that loss of IFNγR1 in glioblastoma cells reduced overall CAR T cell binding duration and avidity. The critical role of IFNγR signalling in susceptibility of solid tumours to CAR T cells is surprising, given that CAR T cells do not require traditional antigen-presentation pathways. Instead, in glioblastoma tumours, IFNγR signalling was required for sufficient adhesion of CAR T cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumours differ in their interactions with CAR T cells and suggests that enhancing binding interactions between T cells and tumour cells may yield improved responses in solid tumours.

Good Health and Wellness: Reflections on Implementing Health Promotion in Indian Country.

In 2014, the Centers for Disease Control and Prevention (CDC) launched "A Comprehensive Approach to Good Health and Wellness in Indian County" (GHWIC) to promote health and chronic disease prevention in tribal communities while facilitating cross-cultural learning and relationship-building. Through GHWIC, CDC aimed to work with American Indian and Alaska Native communities to identify effective health promotion strategies to address chronic disease disparities. Tribal sovereignty, community context, and consideration of tribal histories (e.g., oppression, genocide, and cultural erasure) are key to health improvement efforts and work with tribes. These elements center experience, knowledge, and self-determination to reclaim good health and wellness as Indigenous peoples see it. The Implementation Reflection Project was a qualitative inquiry composed of one-on-one discussions and small group sessions conducted to explore experiences of CDC staff, national partners, and tribal recipients as they implemented GHWIC program activities. The Project documented observations and recommendations for future tribal health funding efforts and identified best practices for effective partnerships with tribes and tribal organizations. Findings centered around tribal experiences with GHWIC, improved program processes, the importance of relationships, and the effects of internal capacity on implementation. Key suggestions for future work with tribal entities included simplifying and clarifying roles, expectations, and administration requirements, and establishing clear and consistent communication between program partners. The approach CDC used with GHWIC recipients was effective and respectful, but room for growth remains. Potential future collaborators in Indian Country should consider these findings when planning health promotion initiatives.