Abstract 5104: Targeting IL-1B synergizes with PD-1 blockade for enhanced T and B cell immune responses and inhibition of early lung cancer development
Authors: Treekitkarnmongkol Warapen , Han Guangchun , Rahal Zahraa , Feng Jiping , Sinjab Ansam , Cascone Tina , Stevenson Christopher S. , Sweeney Cheryl , Edwards Matt , Spira Avrum , Fujimoto Junya , Moghaddam Seyed Javad , Wang Linghua , Kadara Humam 
Published: April 2023

Early immunotherapy with inhibitors of immune checkpoints such as PD-1 has revolutionized lung adenocarcinoma (LUAD) treatment. Still, many patients do not respond or relapse following PD-1 blockade. Tumor-promoting inflammation, such as that mediated by the pleiotropic cytokine interleukin 1 beta (IL-1B), fosters immunosuppression in the tumor immune microenvironment (TIME). Our group and others showed that IL-1B blockade inhibits lung cancer development. We thus hypothesized that addition of IL-1B blockade to anti-PD-1 treatment may enhance outcomes against LUAD. Using a human-relevant, tobacco-associated, mouse model of LUAD development, we compared the effects of combined PD-1 and IL-1B blockade relative to treatment with single-agents (anti-IL-1B or anti-PD-1) and control antibody on early lung tumor development and the TIME. Drugs (anti-PD-1 + anti-IL-1B, anti-PD-1, anti-IL-1B, control IgG) were administered at end of exposure to the tobacco-specific carcinogen NNK, to evaluate effects on formation of early lesions (preventive), or at 3 months post-NNK (prophylactic) to interrogate LUAD development (8 groups). Comprehensive interrogation of the lung ecosystem and the TIME was performed using deep single-cell RNA-sequencing (scRNA-seq) analysis in a subset of the mice (n = 3 to 4) from each of the 8 groups (n = 31 total; 143,897 cells after stringent quality control). Mice treated with combined PD-1 and IL-1B blockade displayed reduced development of lung tumors when compared to animals treated with anti-IL-1B, anti-PD-1, or control antibodies. Fractions of cytotoxic Cd8+ T cells were conspicuously higher and those of tumor cells and exhausted Cd8+ T cells evidently lower in lungs of mice treated with combined PD-1 and IL-1B blockade relative to monotherapy- or control antibody-treated animals. Igha+ plasma cells were strikingly highest in lungs of mice treated with combined PD-1 and IL-1B blockade and nearly absent in monotherapy- and control-treated groups. Lungs of mice treated with combined PD-1 and IL-1B blockade showed higher fractions of Cd80+/Cd86+ memory B cells and, consistently, T follicular helper T cells, while exhibiting reduced fractions of naïve B and Cd24a+/Tgfb1+ B cells suggestive of enhanced activation of B cell responses by the combinatorial treatment. These effects were, overall, present, or much more pronounced, in animals that were prophylactically treated. Flow cytometry analysis of lung tissues and immune profiling of bronchioalveolar lavage fluid overall confirmed augmented immune cell responses by combined PD-1 and IL-1B blockade. Our findings show that blocking IL-1B synergizes with anti-PD-1 in regression of early tumor cells and reversal of immunosuppression. Combined blockade of PD-1 and IL-1B may be a promising strategy for early treatment of lung cancer that warrants further clinical studies.

Citation Format: Warapen Treekitkarnmongkol, Guangchun Han, Zahraa Rahal, Jiping Feng, Ansam Sinjab, Tina Cascone, Christopher S. Stevenson, Cheryl Sweeney, Matt Edwards, Avrum Spira, Junya Fujimoto, Seyed Javad Moghaddam, Linghua Wang, Humam Kadara. Targeting IL-1B synergizes with PD-1 blockade for enhanced T and B cell immune responses and inhibition of early lung cancer development. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5104.