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