| The dynamics of cancer immunosurveillance remain incompletely understood, hampering efforts to develop immunotherapies for cancer. We used flow cytometry and immunohistochemistry to evaluate the evolving in vivo immune response to spontaneous pancreatic ductal adenocarcinoma (PDA) from the inception of preinvasive disease to invasive and metastatic cancer. We characterized this response in several genetically defined mouse models of PDA that differed in the kinetics of disease progression as well as in the complement of initiating mutations. Although there were subtle differences between the various models, the following themes were common: Leukocytes infiltrated prominently around even the lowest grade preinvasive lesions, but immunosuppressive cells including tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg) dominated the early response and persisted through invasive cancer. MDSC tracked specifically with the tumor micro-environment: they were found in all metastases examined including those to diaphragm, liver, lung, and peritoneal wall. MDSC also accumulated dramatically in the spleens of tumor-bearing animals as a result of extramedullary hematopoiesis driven by soluble tumor-derived factors including GM-CSF. Efector CD8+ T cells were scarce in preinvasive lesions, found in only a subset of advanced cancers, and showed little evidence of activation. The lack of tumor-infiltrating effector CD8+ T cells strongly correlated with the presence of intratumoral MDSC with a near mutual exclusion. We also found that MDSC were able to suppress T cell proliferation in vitro. These observations led us to try several experimental approaches to eliminate MDSC in vivo in the hopes of augmenting T cell infiltration and/or activation. The therapeutic regimens tested were not effective at eliminating MDSC in vivo; however, we identified a precursor cell of MDSC in the spleen that expressed c-kit and may represent a better therapeutic target. |
