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Immune Microenvironment Composition Linked to Clinical Outcomes
In the first issue of Cancer Discovery, DeNardo, Coussens and colleagues analyzed lymphocyte and macrophage density from treatment-naive patients with breast cancer and established that an immune signature of high CD68+ tumor-associated macrophage (TAM) infiltration and low cytotoxic CD8+ T-cell infiltration predicted decreased relapse-free survival and overall survival. TAM recruitment was enhanced in patients receiving neoadjuvant chemotherapy, and studies in mice showed that chemotherapy induced the expression of chemokines and cytokines that promoted TAM recruitment, such as CSF1. Pharmacologic blockade of chemotherapy-induced TAM recruitment with a CSF1R inhibitor enhanced CD8+ T-cell infiltration into mouse tumors and sensitized tumors to chemotherapy in a CD8+ T-cell dependent manner. Macrophage and cytotoxic T-cell infiltration as determined by CD68 and CD8 mRNA expression in fine-needle aspirates obtained from patients at diagnosis was predictive of survival and chemotherapeutic response, with high CD68 and low CD8 expression associated with worse outcomes across multiple breast cancer subtypes. This was among the first studies to establish that the overall composition of the immune microenvironment is a predictive biomarker of clinical outcomes. It presaged a host of future studies characterizing tumor immune cell composition in clinical samples and targeting the immunosuppressive tumor microenvironment to enhance therapeutic responses.