Myeloid Cell Interactions Modulate Combination Immunotherapy Outcomes in the Liver Tumor Microenvironment
Therapies that harness the immune system (immunotherapy) have saved the lives of many people with cancer. Unfortunately, most cancers don't respond to standard immunotherapy, especially liver cancers, which are particularly successful in blocking the immune system. A combination of immunotherapies may be necessary to significantly improve outcomes.
The purpose of this project is to develop research models that enable direct observation of the interaction of cancer and immune cells during combination immunotherapy treatments. Cutting-edge 2-photon fluorescence microscopy to enable clear visualization of individual immune and tumor cell interactions has revealed that the actions of distinct immune cell subtypes indicate whether an immunotherapy can control tumor growth. Basic understanding of how tumor-immune interactions occur in the unique tumor environment of the liver are important for the rational design of effective new therapies against advanced liver cancers.
Blocking the interaction between PD-1 on T cells and its ligand PD-L1 leads to impressive responses in a subset of people with cancer. Because of this promise, immune checkpoint inhibition (ICI) therapies that target PD-1 have been approved by the U.S. Food and Drug Administration (FDA) for treatment of hepatocellular carcinoma (HCC). Unfortunately, 80% of patients are unresponsive, largely due to a high degree of immunosuppression cultivated within the solid tumor microenvironment (TME).
Knowledge of the immune mechanisms that support the TME is key for predicting effective responses to ICI. To demonstrate the feasibility of our approach, we used the robust B16 murine melanoma model to optimize our platform for live cell tissue imaging by 2-photon microscopy.
Indeed, using cell-specific fluorescent reporters, we were able to image macrophages and monocytes, dendritic cells, T cells and autofluorescent collagen within subcutaneously implanted B16 tumors and tumor-draining lymph nodes.
We have conducted preliminary studies of combination anti-PD-1 and anti-PD-L1 ICI treatment on B16 tumors. Once inoculated, tumors rapidly grew logarithmically in volume but failed to grow further with the first administration of ICI.
Through analysis, we found that treatment with anti-PD-1 and anti-PD-L1 increased the proportion of CD8+ T cells and decreased the proportion of macrophages.
Within the macrophages, treatment tended to polarize toward the inflammatory MHC-II + M1 subset over that of the immunosuppressive arginase + M2 subset.
Thus, our model demonstrates a correlation between increased M1 macrophage polarization with increased T cell infiltration into the tumor after ICI administration.
Since the liver is a unique immune site with abundant myeloid cells specific to the liver, it is critical to translate understanding of ICI to the context of the liver TME.
To this end, we propose these two aims:
- Specific Aim 1. Determine the impact of anti-PD-1 and anti-PD-L1 ICI on tumor-associated macrophages in the liver TME.
- Specific Aim 2. Determine the impact of oncolytic viroimmunotherapy on monocyte polarization in HCC tumors.