Using PD-1 as a backbone, we found that CD8+ tumor-infiltrating lymphocytes (TIL) had a significantly higher co-expression of PD-1/ICOS and PD-1/CTLA-4 (Fig. 3A) and high levels of PD-1 expression (PD-1hi) compared with normal tissue (Fig. 3B), suggesting a more regulated, chronically antigenic stimulated immune microenvironment in the tumor (38, 39). Here, CTLA4 is linked to neoplasm.