Fig. 2

The Immune Incline. The generation of an effective anti-tumor immune response conceptionally requires overcoming of two additive barriers, namely sufficient immunogenicity to prime a maximal immune response (grey block; comprising stages 1-3 of the immune cycle, Fig. 1), and overcoming the immune suppressive activity at the site of the tumor (red block; comprising stages 4-7 of the immune cycle) that restrict activity of primed, tumor-specific effector cells. While the relative contribution of these barriers may vary between different malignancies and patients, these two barriers comprise a conceptual immune incline (wedge) with a threshold that needs to be reached for ICI to provide clinical benefits (blue broken line; set at an arbitrary and hypothetical level to illustrate the concept). For instance, tumors with higher TMB and corresponding immunogenicity have a higher intrinsic immune activation potential (extent of dark blue part of wedge) than tumors with lower TMB. Conversely, a strongly immune-suppressive TME (left) contributes more to the immune incline than a weakly immune-suppressive TME (right). Accordingly, ICI therapy needs to overcome the difference between the cancer cell intrinsic immune potential (black broken line) and the local immune potential required to reach the threshold for a therapeutic response (indicated by double-headed green arrows). The latter, clinically relevant ICI targets include, (1) effective antigen presentation by DC as part of inducing maximal immune activation (width of grey box) and promoted by stimulation of CD40 and/or inhibition of the CTLA4 and PD1 axis, and (2) maximal inhibition of local immune suppression in the TME (width of red box) by inhibition of the PD1 axis, Tim3, LAG1 and other inhibitor immune checkpoints