Exploring the impact of CD300e in colorectal cancer: insights from obesity-related murine models

Colorectal cancer (CRC) is the second most common cause of cancer-related death. CRC pathogenesis involves dynamic interactions within the tumor microenvironment (TME), influencing tumor development and progression. Tumor-associated macrophages (TAMs) represent the most abundant immune cell type in the TME, which are corrupted by tumor cells, progressively skewing their profile towards an immunosuppressive function, supporting tumor growth. Recent in vitro findings have brought attention to the inhibitory role of CD300e in antigen presentation, suggesting a potential role of the receptor in pathologies involving a defective antigen presentation process, including cancer. Interestingly, CD300e expression has been observed in CRC, specifically by infiltrating monocytes and macrophages. The present study investigated the in vivo role of CD300e in shaping TAMs profile by employing a subcutaneous model of CRC taking advantage of constitutive CD300e knockout (KO) mouse line. CD300e-depletion induced a delay in tumor growth, and the immune profiling of tumor infiltrate revealed that TAMs acquired an immunostimulatory functional profile consisting of high MHC-I and MHC-II expression and strong downmodulation of PD-L1 in the absence of CD300e. Additionally, a higher infiltration of effectors CD8 lymphocytes highly producing IFN-g followed CD300e depletion, suggesting a capability of CD300e ablation to modulates TAMs functional profile, in turn ensuring a proper adaptive anti-tumor immune response. Interestingly, CD300e expression was detected in adipose tissue (AT)-infiltrating macrophages in obese patients, suggesting a potential role of the receptor in different pathological conditions. This hypothesis was supported by the fact that sphingolipids, which are overproduced by obese AT, are considered the potential ligands of CD300e. Given the well-recognized correlation between CRC and obesity, we investigated the in vivo relevance of CD300e in a mouse model mimicking obesity-associated CRC. CD300e absence caused a worsening in high-fat diet (HFD)-induced obese phenotype without affecting tumor development. CD300e depletion entailed increased weight gain, significant AT accumulation, and adipocyte hypertrophy. A highly infiltration of macrophages with a defective lipid clearance function characterized AT of CD300e deficient mice. Accordingly, the same mice displayed marked hepatic steatosis and enhanced lipogenic pathways. Being tumor cells capable of taking up lipids to fuel their survival and sustain their proliferation, it is plausible that excess lipids accumulating in the absence of CD300e may be advantageous for tumor progression. Our results suggest that CD300e could act as a lipid sensor necessary to maintain AT homeostasis during obesity development. Consequently, its absence could negatively impact intestinal health, promoting tumor development. Overall, the present work revealed novel functions of CD300e in different pathological conditions, paving the way for a deeper characterization of the mechanisms underlying its immunomodulatory and metabolic effects. Future research could provide crucial insights into CD300e actions, allowing the development of novel therapeutic approaches targeting CD300e.