CD28 and melanoma: In the absence of PTEN, TCR-mediated activation of T cells is strongly enhanced and thresholds for T-cell activation become less dependent on CD28 co-stimulation.41 Taken together, the above four lines of evidence argue that kinase acivities and pathways that are differentially present in melanoma and NSCLC patients who respond to anti-PD-1 reflect the presence of circulating tumor-specific T cells.38