Aspirin in the era of immunotherapy

Immune checkpoint inhibitors against the PDCD1 (programmed cell death 1, PD-1)-CD274 (PDCD1 ligand 1, PD-L1) axis have shown unprecedented clinical benefits in the treatment of refractory neoplasms [Gentzler R, et al. Immunotherapy. 2016;8:583-600]. Recently, the U.S. Food and Drug Administration (FDA) approved the antiPDCD1 (PD-1) antibody pembrolizumab for treating solid tumors with high-level microsatellite instability (MSI) or mismatch repair deficiency. This approval attracted great attention as the first of an agent based on a tumor biomarker rather than the primary cancer site. Highlevel MSI is commonly present in colorectal carcinomas, and abundant neoantigens due to frequent frameshift mutations have been proposed as a potential explanation of the survival benefits seen with the immune checkpoint blockade in this tumor subtype [1]. However, not all MSIhigh colorectal carcinomas respond to the immunotherapy. The oncogenesis of colon and rectal cancer represents a complex process that is influenced by lifestyle factors, the microbiome, and host cells, potentially leading to not only a unique combination of genetic and epigenetic aberrations but also a distinct microenvironment [2, 3]. Therefore, there exists an important need to identify predictive factors for response to immunotherapy beyond tumor MSI status and to develop effective combination treatment strategies. Aspirin is a common nonsteroidal anti-inflammatory drug (NSAID) that inhibits PTGS1 (cyclooxygenase-1) and PTGS2 (cyclooxygenase-2), and regular aspirin use has been shown to reduce colorectal cancer incidence and mortality [Drew DA, et al. Nat Rev Cancer. 2016;16:173186]. Taking the inter-tumor heterogeneity into account, large cohort studies suggest that survival benefits from postdiagnosis aspirin use are pronounced for colorectal cancer with PTGS2 overexpression or activating PIK3CA mutations [4, 5] [Domingo E, et al. J Clin Oncol. 2013:31:4297-4305; Gray RT, et al. Clin Transl Gastroenterol. 2017:8:e91], supporting the potential of these molecular alterations as tumor biomarkers for response to adjuvant aspirin therapy. Notably, these findings provide population-based evidence for the underlying mechanisms by which aspirin may suppress colorectal cancer progression: i.e., aspirin may reduce colorectal cancer mortality by inhibiting PTGS2 and prostaglandin E2 (PGE2) synthesis that are enhanced by activated PI3K signaling. Beyond these potential antitumor effects associated with inhibition of oncogenic signaling pathways, accumulating evidence points to immune-enhancing effects of aspirin on adaptive and innate immune response, including T cell-mediated antitumor immunity [6]. Recently, we reported a U.S. population-based study which suggested a stronger survival association of postdiagnosis aspirin use in colorectal cancer with lower-level CD274 (PD-L1) expression than in cancer with higher-level CD274 expression (Figure 1) [7]. This study was motivated by experimental data supporting a synergistic effect between aspirin and anti-PDCD1 antibody [8]. In the study by Zelenay et al. [8], PTGS (cyclooxygenase)-induced PGE2 was shown to play a key role in suppressing anti-tumor immune response and promoting growth of cancer cells through increased levels of inflammatory mediators. In a mouse model, PTGS inhibition via aspirin synergized with the immune checkpoint blockade toward immune eradication of Editorial