Fig. 1
From: Checkpoint inhibitors in melanoma and early phase development in solid tumors: what’s the future?
Hypothetical model about how BRAFV600 mutation in melanoma cells could affect the tumor microenvironment and response to ipilimumab and combination of ipilimumab and nivolumab. a The BRAFV600 mutation is able to upregulate the expression of CD73 on the melanoma cells [16] which is responsible of the increase of adenosine into the tumor microenvironment (TME). Adenosine is strongly immunosuppressive affecting almost all the immune cells. In non small cell lung cancer (NSCLC) the EGFR mutation is able to make a similar condition [14]. b The detailed action of adenosine on T regulatory cells (Treg), and T effector cells (Teff). Adenosine, binding the A2A receptor (A2AR), is able to expand and activate Treg cells increasing the nuclear expression of FoxP3; at the same time inactivating Teff cells through the increase of CTLA-4 and PD-1 expression, and decrease of IL-2 production and CD25 expression, proliferation, TH1 and TH2 development, TH17 generation. The result of these pleotropic effects of adenosine is a “stuck” TME with high number of activated Treg cells and exhausted T cells. c In the immune suppressed TME induced by adenosine, anti-PD-1 is able to remove the blockade caused by the activation of PD-1/PD-L1 pathway and Teff cells can kill melanoma cells. In NSCLC, the EGFR mutation is also responsible for the low expression IFN-γ signature [14] contributing at the low effect of anti-PD-1 in this group of patients. d Higher dosage of ipilimumab (low dosage of ipilimumab does not seem to affect the TME [8]), or the addition of ipilimumab to nivolumab, may trigger an ADCC mechanism of action removing the activated Treg cells and improving the action of ipilimumab as single agent or in combination with nivolumab where there is the additional important activation of Teff cells mediated by anti-PD-1