A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

Figure 3. Tumor Immunity in the Microenvironment Classification Four different TME groups with potential implications for mechanism and therapy have been identified according to B7-H1 (PD-L1) expression and the presence of TILs in tumor biopsies: I, B7-H1-negative tumors without TILs, considered immunological ignorant because immune cells do not accumulate at the tumor site, II, B7-H1-positive tumors with TILs, considered a paradigm of adaptive resistance of tumors mediated by the B7-H1/PD-1 pathway, III, B7-H1-negative tumors with TILs, considered a situation of tolerance because TILs are present, but they do not induce B7-H1 expression in the tumor microenvironment through IFN-g production, and IV, B7-H1-positive tumors without TILs, considered as a scenario of intrinsic induction of B7-H1 expression in tumor cells through oncogenic pathways that may be susceptible to be targeted. Groups I, III, and IV can be converted into group II through different strategies, synergizing with the action of anti-PD therapies that are more effective in the presence of TILs and B7-H1 expression.