Fig. 4

Dynamic interaction of the tumor with the anti-tumoral immune response induced by immune checkpoint blockade. The immune response directed against the tumor may induce changes in tumor cells that will participate in the regulation of this response. As, such, tumor cells are active regulators of the immune response directed against the TME. Tumor cells have the potential to both enhance or weaken the immune system (e.g. through the upregulation of genes involved in the antigen-presentation machinery in response to INF-gamma), or (e.g. through the expression of PD-L1 or the upregulation of pathways actively participating to the exclusion of T cells from the TME) respectively. The resulting immune response will in turn contribute to dynamic changes in tumor clonal composition. An effective anti-tumoral immune response will translate into the elimination of tumor cell clones as a function of their immunogenicity. This may in time select for pre-existing or de novo immune resistant clones that have the capacity to thrive in spite of the immune pressure induced by ICI, leading to secondary immune resistance