Negative impact of myeloid-derived suppressor cells on CD8 effector T cell trafficking within the tumor microenvironment (TUM4P.924)

Abstract

Abstract The success of immunotherapy and, unexpectedly, chemotherapy and radiation hinges on cytotoxic T cells gaining access to tumor targets. These observations have prompted interest in developing strategies to improve T cell trafficking in tumors. Here, we report that the ability of tumor vessels to respond to IL-6-dependent preconditioning regimens that boost CD8 effector T cell homing is temporally and inversely related to the expansion of myeloid-derived suppressor cells (MDSC) within the tumor microenvironment. Using real-time intravital imaging and immunofluorescence histology, IL-6 therapies were shown to convert vessels from T cell-low to -high recruitment sites in murine tumors with minimal MDSC infiltration (i.e., CT26 colorectal, B16 melanoma, EMT6 mammary tumors). This conversion requires induction of the ICAM-1 trafficking molecule on tumor vessels. Conversely, mammary (4T1, AT-3 and PyMT-MMTV) and pancreatic (Pan02) tumors with high MDSC burdens were refractory to IL-6 therapies, but became responsive after acute MDSC depletion. To further investigate contributions of MDSC to poor trafficking, IL-6-responsive tumors were admixed at a ratio of 2:1 with MDSC from tumor-bearing mice. Sustained elevation of MDSC in admixed tumors resulted in failure to support increased T cell trafficking in response to IL-6-dependent therapy. Taken together, these findings identify a novel role for MDSC in immune evasion by limiting T cell trafficking at tumor vascular loci.