Despite still unclear, several other mechanisms and immune regulatory pathways seem to be involved in the response to PD-1/PD-L1 pathway blockade such as the PD-L2 expression, a second known ligand for PD-1, the PD-1 expression on T-lymphocytes, and the discovery of immunogenic neo-antigens, encoded by gene mutations called ‘passenger’ that do not trigger the cancer development but play an important role in immunogenicity [34, 51–53]. The gene discussed is PDCD1LG2; the disease is cancer.