LAUSR

The composition of the tumor immune microenvironment dictates responsiveness to cancer immunotherapies, though discrete biomarkers to predict responsiveness are yet to be defined. Much of the focus of the field of biomarker research has been on the spatial distribution and activation status of CD8 T cells when defining whether a tumor is “inflamed” and potentially responsive to immunotherapy. However, the majority of the leukocyte composition of most tumors, including nonsmall cell lung cancer (NSCLC), is of myeloid, not lymphoid, origin, and these cells appear to play a role in dictating therapeutic efficacy. Through single-cell analysis at the proteomic and transcriptomic level we can define the resident myeloid populations within the tumor, to determine the role these subsets play in developing an immunosuppressive tumor microenvironment, and identify potential therapeutic targets. Through mass cytometry our group has demonstrated selective depletion of resident alveolar macrophages, with enrichment of a distinct tumorassociated macrophage (TAM) population within the tumor. Single-cell RNA sequencing confirms the disparate transcriptome of these TAMs contrasted with resident lung macrophages, and direct concordance between a defined monocyte-derived TAM and T regulatory cell enrichment, as well as T effector cell dysfunction. These inhibitory myeloid subsets present a potential therapeutic target to further potentiate current immunotherapy approaches. We have identified multiple chemokine and cytokine pathways that may be integral to recruitment and maintenance of this immunosuppressive milieu, and validated dependence on these pathways in preclinical studies. To investigate the role of two of thesemyeloid-recruitment pathways in vivo in humans, we have designed a neoadjuvant “window-of-opportunity” trial that will evaluate the synergy of PD-1 blockade with disruption of the CCR2/5 or interleukin-8 mediated myeloid recruitment and retention within early-stage NSCLC lesions.