CTLA4 and lymphopenia: Several mechanisms may account for lymphopenia detected in metastatic cancer patients; i) destruction of lymphocytes induced by tumor cells expressing pro-apoptotic ligands [112], ii) reduced capacity of lymphocytes to respond to TCR stimulation due to an altered expression of the ζ chain of the TCR [113], iii) a high proportion of CTLA-4-expressing Tregs favoring immunosuppression [114] or iv) activation induced cell death (AICD) [115].