Malignancy and implication of immune checkpoints inhibitors (ICIs)
Malignant transformation is characterized by the ability to avoid the normal regulatory mechanisms of cell growth, division, and immune-mediated cell death. Indeed, malignant cells are capable of upregulating immune checkpoint proteins – increasing the expression of both PD-L1 as well as CTLA-4. Increased PD-L1 expression has been observed in multiple malignancies, particularly in melanoma, non-small cell lung cancer (NSCLC), and ovarian cancer.44Preclinical evidence from in vitro and in vivo murine models as well as from clinical trials have shown that malignancy-invading T-lymphocytes can be inhibited by malignancy-related expression of CTLA-4 or PD-1.45-47 Ipilimumab, a CTLA-4 inhibitor, was the first treatment demonstrated to prolong overall survival in patients with advanced melanoma across several clinical trials.17,48 Following this finding, the application of PD-1 inhibitors in patients with melanoma, NSCLC, or renal cell carcinoma (RCC) also demonstrated significant clinical efficacy, on par with those treated with CTLA-4 inhibitors.49-54 Given the distinct mechanisms (Table 1) of CTLA-4 and PD-1 blockade with respect to T-lymphocyte regulation, dual-blockade of both CTLA-4 and PD-1 have been suggested as therapeutic option for advanced malignancies, due to the presumed additive or synergistic, non-overlapping mechanisms.6,55-57Indeed, prior studies have demonstrated that CTLA-4 inhibition induced a proliferative signal mainly in a subset of T-lymphocytes, whereas PD-1 inhibition is associated with cytolysis and natural killer cell function with several preclinical studies and clinical trials demonstrating enhanced antitumor responses using dual ICI therapy as compared to ICI monotherapy, with the potential caveat of increased toxicity.11,13,58-62