Abstract
Therapeutic options for non-small cell lung cancer (NSCLC) treatment have changed dramatically in recent years with the advent of novel immunotherapeutic approaches. Among these, immune checkpoint blockade (ICB) using monoclonal antibodies has shown tremendous promise in approximately 20% of patients. In order to better predict patients that will respond to ICB treatment, biomarkers such as tumor-associated CD8+ T cell frequency, tumor checkpoint protein status and mutational burden have been utilized, however, with mixed success. In this study, we hypothesized that significantly altering the suppressive tumor immune landscape in NSCLC could potentially improve ICB efficacy. Using sub-therapeutic doses of our Salmonella typhimurium-based therapy targeting the suppressive molecule indoleamine 2,3-dioxygenase (shIDO-ST) in tumor-bearing mice, we observed dramatic changes in immune subset phenotypes that included increases in antigen presentation markers, decreased regulatory T cell frequency and overall reduced checkpoint protein expression. Combination shIDO-ST treatment with anti-PD-1/CTLA-4 antibodies enhanced tumor growth control, compared to either treatment alone, which was associated with significant intratumoral infiltration by CD8+ and CD4+ T cells. Ultimately, we show that increases in antigen presentation markers and infiltration by T cells is correlated with significantly increased survival in NSCLC patients. These results suggest that the success of ICB therapy may be more accurately predicted by taking into account multiple factors such as potential for antigen presentation and immune subset repertoire in addition to markers already being considered. Alternatively, combination treatment with agents such as shIDO-ST could be used to create a more conducive tumor microenvironment for improving responses to ICB.
Highlights
Non-small cell lung cancer (NSCLC) tumors contain large percentages of T cells (25–46% of theCD45+ fraction), many expressing tumor antigen-specific T cell receptors (TCRs) [1,2]
Greater benefit was seen with the combination of ipilimumab and nivolumab, which showed significantly improved overall survival compared to chemotherapy and nivolumab alone [15], resulting in recent FDA approval for frontline treatment of metastatic non-small cell lung cancer (NSCLC) with the ipilimumab and nivolumab combination
Therapeutic shIDO-Salmonella Typhimurium (ST) treatment has been shown to induce a predominantly cytotoxic neutrophil response that is directly involved in rapid clearance of tumor cells [22,35]
Summary
Non-small cell lung cancer (NSCLC) tumors contain large percentages of T cells Greater benefit was seen with the combination of ipilimumab and nivolumab, which showed significantly improved overall survival compared to chemotherapy and nivolumab alone [15], resulting in recent FDA approval for frontline treatment of metastatic NSCLC with the ipilimumab and nivolumab combination These cell surface molecules, and a few others, constitute the immune “checkpoint” proteins. Found in tumor tissue and draining lymph nodes, have high expression of CTLA-4 and Lag-3 that facilitate suppression of dendritic cells (DCs) and T cells through direct cell-to-cell contact They secrete immunosuppressive cytokines such as IL-10, transforming growth factor β (TGF-β), and IL-35, which downregulate IFNγ responses, inhibit antigen presentation by APCs, and impair T cell proliferation [21]. Our ability to demonstrate synergy between shIDO-ST and ICB treatment may support their combination as a strategy to enhance response rates in NSCLC patients [38,39]
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