Abstract 3790: Human tumor-infiltrating monocytes/macrophages do not predominantly inhibit tumor-specific effector T cell responses in early-stage lung cancer: The role of macrophage versus tumor PD-L1

Abstract

Abstract Our current understanding of tumor-associated monocyte/macrophage lineage cells (MMLC) as being immunosuppressive is based largely on murine tumor models that generated a widespread interest in targeting these cells therapeutically. Unfortunately, this approach has not yet been successful in many clinical trials. One potential explanation is that there are fundamental differences between mice and humans in tumor evolution and immunity that might impact the function of human MMLC, limiting the success of myeloid cell-related therapies. Moreover, despite recent successes with checkpoint blockade therapy, the contribution of PD-L1 expressed on MMLC to T cell suppression in humans remains unclear. Thus, the overall purpose of this study was to determine the phenotypic composition of monocyte-macrophage cell lineage in a large cohort of early stage (resected) human lung tumors and delineate how different cell populations of this lineage regulate the effector phase of tumor-specific T cell responses. In addition we also explored the role of MMLC-expressed PD-L1 by interrogating the tripartite functional interactions between tumor-specific effector T cells, PD-L1+ or PD-L1- tumor cells, and TAM that possess a varied surface PD-L1 expression. Phenotypically, we find that (i) MMLC are not the predominate cell population of infiltrating leukocytes within the early-stage lung tumors, (ii) tumor MMLC consist primarily of tumor-associated macrophages (TAM), (iii) the TAM phenotype is complex and does not fit the conventional M1 and M2 phenotype denominations, (iv) TAM are able to co-express T cell co-inhibitory and co-stimulatory receptors. Functionally, MMLC are not primarily suppressive, but have diverse effects, including stimulation of the effector phase of tumor-specific T cell responses. Mechanistically, TAM-expressed PD-L1 (in contrast to tumor-expressed PD-L1), does not inhibit the interaction between tumor-specific effector T cells and tumor cells, but does protect TAMs expressing a tumor antigenic peptide/MHC class I complex from being killed by effector T cells recognizing the cognate peptide on the tumor. These data provide new insights into the phenotype of tumor MMLC and functional cross-talk between TAM, tumor-specific T cells, and tumor cells. Our results show that the prevailing premise that TAMs are predominantly immunosuppressive does not apply to early-stage human lung cancer and thus the current MMLC-targeted approaches would not be helpful in majority of early-stage lung cancer patients. Citation Format: Jason Stadanlick, Abhishek Rao, Sunil Singhal, Michael Annunziata, Pratick Bhojnagarwala, Shaun Obrien, Edmund Moon, Edward Cantu, Gwenn Danet-Desnoyers, Hyun-Jeong Ra, Leslie Litzky, Wayne W. Hancock, Steven M. Albelda, Evgeniy Eruslanov. Human tumor-infiltrating monocytes/macrophages do not predominantly inhibit tumor-specific effector T cell responses in early-stage lung cancer: The role of macrophage versus tumor PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3790.