In recent years, advances in cancer immunotherapy make it possible to induce tumor-specific immune responses in patients treated with various types of cancer immunotherapy. However, despite these successes, the proportion of patients who benefit clinically from these treatments remains small. It is clear that the tumor microenvironment may provide protection of tumors even against potent cytotoxic T cell (CTL) responses. Inflammation associated with the tumor microenvironment plays an important role in the development and progression of lung cancer. In the context of an inflammatory response myeloid cells are the primary recruited effectors. Production of reactive oxygen (ROS) and nitrogen (RNS) species is one of the major characteristics of all activated myeloid cells. The formation of the free radical peroxynitrite (PNT) is the main result of interaction between superoxide and nitric oxide. Nitration of tyrosine residues has long been recognized as a marker of PNT activity. In addition, PNT can react directly with cysteine, methionine and tryptophan. A substantial number of studies have demonstrated high levels of nitrotyrosine (NT) in lung cancer. Recently, we have proposed a novel concept that may explain the role of inflammation in tumor escape. The tumor-infiltrating myeloid cells, particularly myeloid-derived suppressor cells, can induce nitration of MHC class I molecules on tumor cells, making them unable to effectively bind and retain peptides and thus rendering the tumor cells resistant to antigen-specific CTLs. This concept suggests that tumors may escape immune control even if potent CTL responses against the tumor-associated antigens were generated either by vaccines, T-cell transfer, or checkpoint inhibitors. It also suggests that this escape can be diminished by blocking the PNT production using pharmacological inhibitors of ROS or RNS. Based on our previous and preliminary data we propose that inhibition of ROS and RNS in the tumor microenvironment can enhance the effect of cancer immune therapy. In this application we will test this hypothesis.
Specific aim 1. To determine the mechanism of peroxynitrite effects on tumor escape;
Specific aim 2. To determine in mouse tumor models the combine effect of a blocking PD1 antibody with a novel triterpenoid RTA 408;
Specific aim 3. To determine clinical significance of up-regulation of reactive oxygen and nitrogen species in lung tumors.
This proposal addresses in preclinical setting important clinical problem - tumor escape from immune therapy. We will investigate the basic mechanism of this phenomenon, test new approaches to its correction in relevant mouse models of lung cancer and determine its clinical relevance using samples from lung cancer patients.