Abstract

The goal of all immunotherapeutic approaches against solid tumours is the induction and expansion of tumour infiltrating T lymphocytes (TILs) capable of invading tumour mass and kill transformed cells. Unfortunately, in many tumours TILs are unable to reach the core of the tumour and concentrate at the border of the neoplastic lesion. Several barriers can limit complete trafficking and migration of lymphocytes within cancerous tissues. We evaluated the possibility that reactive nitrogen species (RNS) could affect chemokine biology and contribute to keep TILs distant from the tumour core. Chemokines are small cytokines with selective chemoattractant properties, coordinating the homeostatic circulation of leukocytes as well as their movement to sites of either inflammation or injury. Deregulated expression of chemokines and their receptors is a signature of many diseases, including autoimmunity and chronic inflammation, as well as immunodeficiency and cancer. We found that the chemoattractants CXCL12, CCL21, and CCL2 lost their ability to recruit T lymphocytes when exposed to peroxynitrite, a RNS produced within tumour microenviroment. However, the modified CCL2 chemokine retained its capacity of recruiting myeloid cells. These data indicate that RNS-altered chemokines modify the tumour microenvironment and favour immune escape by attracting tumour-promoting myleoid cells while restraining access to antitumor T lymphocytes. Based on our findings, drugs controlling the in situ production of RNS might be useful to aid immunotherapeutic approaches for the treatment of cancer, by creating a favourable tumour environment for lymphocyte recruitment and activation. Following an extensive in vitro and in vivo screenings, we developed novel small molecules aimed at interfering with multiple, interconnected metabolic pathways leading to RNS generation in the tumour microenvironment. Pre-conditioning of tumour microenvironment with novel drugs that inhibited RNS production facilitated CTL invasion of the tumour and promoted an effective cancer immunotherapy. These results unveil an unexpected mechanism of tumour evasion and introduce new avenues for immunotherapy of tumours.