Myeloid cells in systemic immune reactions during cancer

Abstract

The immune system plays diverse roles during cancer—it can be protective against tumor growth, yet it may also foster cancer progression in some settings. Anti-cancer immunotherapy can simultaneously trigger both productive anti-tumor immune responses and undesired immune related adverse events (irAEs) in non-malignant tissues. How myeloid cells influence outcomes in cancer and therapy remains incompletely understood. Immunotherapies activate the immune system to fight cancer. When successful, they tend to foster a T helper type (Th)-1-polarized cellular immune response in the tumor, involving interleukin (IL)-12 production from myeloid cells (namely dendritic cells, or DCs) and interferon (IFN)-y production from lymphocytes. This response drives forward antigen-specific rejection of cancer cells. Whether similar processes drive irAEs in tumor-free tissues is not known. We therefore investigated mechanisms of irAEs in non-malignant tissue following anti-cancer immunotherapy. Using anti-CD40 treatment in mice as a model of Th1-promoting immunotherapy, we identified both similar and distinct processes occurring in cancerous and non-cancerous tissues. While Th1 cytokine activation was critical for both tumor control and toxicity of a tumor-free tissue site (the liver), the key myeloid cells players were distinct. DCs were required for tumor control; yet liver pathology depended on activation of tissue resident macrophages and a pathological neutrophil response. We found evidence of similar processes occurring in cancer patients experiencing irAEs. Our findings suggest distinct mechanisms of toxicity and anti-tumor immunity following Th1 immunotherapy. In a separate line of investigation, we established an approach for in vivo manipulation and study of neutrophils. Neutrophils can exert pro-tumoral functions, and they can exacerbate irAEs; therefore, targeting these cells could limit detrimental immune processes during cancer and immunotherapy. However, an appreciable level of neutrophil heterogeneity exists in both mice and humans, and important anti-tumoral neutrophil functions have also been identified. Therefore, it may be advantageous to selectively modulate molecular targets implicated in deleterious neutrophil functions, rather than targeting these cells holistically. Approaches to interrogate neutrophil-expressed genes in vivo are limited. We therefore developed a system to modulate neutrophil-associated targets in mice using CRISPR. This system enables stable and efficient editing of neutrophil-expressed genes, and it should be useful for interrogating the roles of defined neutrophil subpopulations during cancer. Together, these mechanistic studies and technical efforts hold implications for advancing our understanding of myeloid cell functions during cancer and immunotherapy. They may ultimately open doors to the development of therapeutic interventions based on modulating myeloid cell biology.