Despite the accumulation of PD1+CD8+ cells in peripheral lymphoid organs of CLL patients, PD-1/PD-L1 blockade alone has shown limited clinical efficacy, with the exception of the most aggressive disease development, Richter’s transformation [45], suggesting that the neutralization of the PD-1 inhibitory signaling axis may not be sufficient to reactivate the CTL anti-tumoral functions, and pointing out the relevant implication of exhaustion molecules other than PD-1, such as CTLA-4 and LAG-3 [8, 46, 47], in restraining CTL functions. This evidence concerns the gene CTLA4 and B-cell chronic lymphocytic leukemia.