Abstract A007: Assessing immunoprevention efficacy of an agonist of CD137 pathway in a tobacco carcinogen-induced lung cancer preclinical model

Abstract

Abstract Purpose: Lung cancer is the leading cause of cancer-related deaths worldwide. Cigarette smoking is the primary risk factor for lung cancer and is linked to 80-90% of lung cancer deaths according to the Centers for Disease Control (CDC). The most carcinogenic component of tobacco smoke is NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone). SA-4-1BBL is a novel CD137 receptor agonist that has shown cancer immunoprevention efficacy in transplantable preclinical tumor models by invoking an innate immune surveillance mechanism involving CD4+ CD44+ T and NK cells. As a preclinical model for high-risk populations, we evaluated the immunoprevention efficacy of SA-4-1BBL in lung tumor formation induced by NNK. Experimental Procedures: A/J female mice were used as a preclinical model for lung cancer immunoprevention due to their susceptibility to tobacco-carcinogen-induced lung cancer. A/J mice were i.p. injected with NNK weekly for eight consecutive treatments. The mice were also treated s.c. with 100 µg SA-4-1BBL twice, two weeks apart on weeks 6 and 8 of NNK treatment. Animals were monitored for 21 weeks and euthanized to harvest the lung and lung-draining lymph nodes for histology (H&E staining and PCNA immunofluorescence staining). In separate groups, mice were treated with a depleting antibody to CD4 twice two weeks apart on weeks 6 and 8 of NNK treatment to investigate the role of CD4+ immune cells in cancer immunoprevention. Results: NNK treatment resulted in lung tumor formation as assessed by PCNA immunofluorescence staining in all saline-injected control mice by the 21-week experimental end-point. Treatment with SA-4-1BBL resulted in significantly fewer macroscopic and microscopic tumor numbers than the control group (p < 0.01). Animals treated with SA-4-1BBL and subjected to CD4+ cell depletion showed similar numbers of macroscopic and microscopic lung tumors to the vehicle group. Conclusions: Prophylactic treatment with SA-4-1BBL significantly prevents NNK-induced lung tumor formation and CD4+ immune cells play a critical role in the observed immunoprevention efficacy of SA-4-1BBL. Supported by a grant from DOD LC190524 to Esma S. Yolcu. Citation Format: Ayse Ece Gulen, Mohammad Tarique, Vahap Ulker, Evrim Agca, Haval Shirwan, Esma S. Yolcu. Assessing immunoprevention efficacy of an agonist of CD137 pathway in a tobacco carcinogen-induced lung cancer preclinical model [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A007.