These results provide the rationale for co-inhibiting TIGIT together with PD-1 and/or LAG-3; for the monitoring of circulating PD-1+TIGIT+CD8+T-subsets or of LAG-3+TIGIT+TILs on melanoma biopsies as early unfavorable cellular biomarkers of an anti-PD-1 response; and for activating CD226 in Tregs together with TIGIT blockade, to counteract Treg suppression in melanoma patients. The gene discussed is CD8A; the disease is melanoma.