Figure 1.

Masking of chemokine signals through intratumoral production of RNS. Metabolism of l-Arginine in the tumor by arginase and iNOS from myeloid or tumor cells leads to the generation of RNS, such as peroxynitrite, inside of the tumor microenvironment (left). This results in the nitrotyrosinylation of proteins, including the chemokine CCL2 (n-CCL2), in the tumor microenvironment. Because n-CCL2 binds to its receptor (CCR2) with much lower affinity than the unmodified version, it prevents n-CCL2 from acting as a strong chemoattractant signal for antitumor T cells (top right). However, myeloid cells express higher levels of CCR2 receptor and are still able to migrate toward n-CCL2 gradients. When the small molecule inhibitor of RNS production AT38 is administered, it blocks peroxynitrite formation and subsequent nitrotyrosinylation of CCL2. This restores deep T cell infiltration into the tumor, enhancing the effectiveness of both adoptive T cell therapy and endogenous antitumor responses (bottom right).