Despite advances in diagnosis and treatment, cancer is the second leading cause of death in the United
States. The discovery and targeting of adaptive immune checkpoints (like PD-1 and CTLA4) has been a boon
to cancer patients. Unfortunately, only a subset of patients will respond and those that do often relapse. In an
attempt to improve the efficacy of adaptive immune targeted therapy, several clinical trials have been proposed
or are underway, exploring the combination of checkpoint blockade with chemotherapy. One rationale for
combination therapy is that chemotherapy induces immunogenic tumor cell death which provides robust
activation of the anti-tumor response by releasing neo-antigens and Damage Associated Molecular Patterns
(DAMPs) that initiate the innate pro-inflammatory response.
We discovered and characterized a novel innate immune checkpoint utilized by tumor cells to suppress the
immune response during chemotherapy. We found that tumor secreted proteins bind and activate the
macrophage Mer receptor, leading to a reduction in the expression of the key Toll-Like Receptor (TLR) adapter
protein MyD88. In the absence of MyD88, macrophages are no longer able to respond to DAMP/TLR signaling,
effectively preventing the pro-inflammatory response during chemotherapy. This suppressive mechanism is
characteristic of tumors of diverse origins including melanoma, lung, pancreas and breast cancers.
Our mechanistic studies have identified that ligand-activated macrophage Mer induces ternary complex
formation, increasing the association of Mer, Stat1 and a phosphatase known as PTP1b. This complex
reduces the phosphorylation and nuclear translocation of Stat1 which leads to a decrease in MyD88
expression. Treating with a PTP1b inhibitor blocks this immune suppressive process and restores DAMP-
mediated activation in vitro and in vivo. Combining PTP1b inhibition with chemotherapy causes ~50%
decrease in tumor growth in multiple murine cancers, including chemotherapy resistant models.
We hypothesize that by targeting the Mer:PTP1b axis, we may be able to improve the innate, and
subsequent adaptive, immune response during chemotherapy. To test our hypothesis we propose to 1)
determine the regulatory mechanism governing tumor secretion of Mer ligands and whether their expression in
human tumors is predictive of chemotherapy response, 2) identify which forms of chemotherapy yield the most
robust immune activation in combination with PTP1b inhibition and 3) ascertain the effects of
chemotherapy/PTP1b inhibition combination therapy on the adaptive immune response.