Since CHI3L1 null mutation or a-CHI3L1 neutralizing antibody treatment reduced metastatic spread (28, 29), they do not determine if the inhibition of ICOS and ICOSL and or the induction of CTLA-4 are due to the direct effects of CHI3L1 or due to the decreased metastatic spread of melanoma. This evidence concerns the gene ICOS and melanoma.