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Rectal cancer constitutes over one-third of all colorectal cancers (CRCs) and is one of the leading causes of cancer-related deaths in developed countries. In order to identify high-risk patients and better adjust therapies, new markers are needed. Systemic inflammatory response (SIR) markers such as LMR, NLR, and PLR have proven to be highly prognostic in many malignancies, including CRC; however, their roles in locally advanced rectal cancer (LARC) are conflicting and lack proper validation. Sixty well-selected patients with LARC treated at the Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw, Poland, between August 2017 and December 2020 were prospectively enrolled in this study. The reproducibility of the pre-treatment levels of the SIR markers, their correlations with clinicopathological characteristics, and their prognostic value were evaluated. There was a significant positive correlation between LMR and cancer-related inflammatory infiltrate (r = 0.38, p = 0.044) and PD-L1 expression in tumor cells, lymphocytes, and macrophages (combined positive score (CPS)) (r = 0.45, p = 0.016). The PLR level was correlated with nodal involvement (p = 0.033). The SIR markers proved to be only moderately reproducible and had no significant prognostic value. In conclusion, the LMR was associated with local cancer-related inflammation and PD-L1 expression in tumor microenvironments. The validity of SIR indices as biomarkers in LARC requires further investigation.

Abstract Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets. Here, we report that VPS4B gene, encoding an ATPase involved in ESCRT‐dependent membrane remodeling, is such a passenger gene frequently deleted in many cancer types, notably in colorectal cancer (CRC). We observed downregulation of VPS4B mRNA and protein levels from CRC patient samples. We identified VPS4A paralog as a synthetic lethal interactor for VPS4B in vitro and in mouse xenografts. Depleting both proteins profoundly altered the cellular transcriptome and induced cell death accompanied by the release of immunomodulatory molecules that mediate inflammatory and anti‐tumor responses. Our results identify a pair of novel druggable targets for personalized oncology and provide a rationale to develop VPS4 inhibitors for precision therapy of VPS4B‐deficient cancers.