Metabolic regulation has been proven to play a critical role in T cell antitumor immunity. However, cholesterol metabolism as a key component of this regulation remains largely unexplored. Herein, we found that the low-density lipoprotein receptor (LDLR), which has been previously identified as a transporter for cholesterol, plays a pivotal role in regulating CD8+ T cell antitumor activity. Besides the involvement of cholesterol uptake which is mediated by LDLR in T cell priming and clonal expansion, we also found a non-canonical function of LDLR in CD8+ T cells: LDLR interacts with the T-cell receptor (TCR) complex and regulates TCR recycling and signaling, thus facilitating the effector function of cytotoxic T-lymphocytes (CTLs). Furthermore, we found that the tumor microenvironment (TME) downregulates CD8+ T cell LDLR level and TCR signaling via tumor cell-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) which binds to LDLR and prevents the recycling of LDLR and TCR to the plasma membrane thus inhibits the effector function of CTLs. Moreover, genetic deletion or pharmacological inhibition of PCSK9 in tumor cells can enhance the antitumor activity of CD8+ T cells by alleviating the suppressive effect on CD8+ T cells and consequently inhibit tumor progression. While previously established as a hypercholesterolemia target, this study highlights PCSK9/LDLR as a potential target for cancer immunotherapy as well.

Gastric plexiform fibromyxoma (PF) is a rare mesenchymal tumor with a histologically distinctive multinodular pattern, dissimilar to conventional gastrointestinal stromal tumor (GIST). The current study presents one case of gastric PF, and one case of GIST with a platelet-derived growth factor receptor α (PDGFRA) mutation mimicking PF, and discusses their differential diagnoses. The two patients were a 51-year-old male with PF and a 47-year-old female with GIST, each of whom presented with an occupying lesion in the gastric antrum. Histologically, the two cases shared a rare and approximately unanimous morphological pattern of a prominent multinodular and plexiform figuration in the gastric wall, including mucoid matrix, short spindle cells and small caliber vascular elements, and areas of stromal tumor cells exhibited an epithelioid appearance. Immunohistochemistry revealed that the PF tumor cells were positive for smooth muscle actin (SMA), but negative for mast/stem cell growth factor receptor (KIT), GIST-1 (DOG1), cluster of differentiation (CD) 34, S-100, desmin and cytokeratin AE1/AE3. The case of GIST expressed KIT and DOG1, but was negative for SMA, CD34, S-100, desmin and AE1/AE3. In addition, the GIST case, which was observed to harbor a D842V mutation in exon 18 of PDGFRA, was demonstrated to be genetically distinct from PF. The cases presented in the current study were uncommon in that GIST exhibited a plexiform appearance that mimicked the histology of the rare PF tumor; therefore, GIST must be considered and discounted first when determining a differential diagnosis for a gastrointestinal mesenchymal neoplasm.

BackgroundMismatch repair proficient colorectal cancer (pMMR CRC) lacks effective treatments and has a poor prognosis, which can be attributed to the complexity of tumor microenvironment. The coordinated function of immune cells is vital to anti-tumor immunity. However, the spatial characteristics of immune cells in the pMMR CRC immune microenvironment and their relationship with clinical prognosis are not fully understood. Meanwhile, the immune modulatory effect of neoadjuvant chemotherapy (NCT), which is the first-line treatment of pMMR CRC, needs further investigation. Therefore, this study aims to explore the spatial dynamics of immune cells and its prognostic value in pMMR CRC.MethodsWe analyzed the various immune cells in formalin-fixed, paraffin-embedded tumor tissues which were collected from 77 patients with stage II/III of pMMR CRC, including 39 non-NCT treated and 38 NCT treated patients. We used the optimized multiplex immunohistochemistry (mIHC) to identify and quantify the density, type and location of immune cells in pMMR CRC. Multivariate survival analysis was performed to assess the relationship of immune profiles and clinical prognosis of pMMR CRC patients.ResultsThe densities of most T cell subsets, B cells and macrophages were higher in the central region of the pMMR CRC than in the invasion margin. Tumor infiltrating lymphocytes (TILs), especially the infiltration of CD4+ GzmB+ T cells in the central region of the tumor was identified to be positively correlated with the prognosis of the patients. Multivariate analysis confirmed that CD4+ GzmB+ T cells population was an independent predictor of disease-free survival (DFS) in non-NCT group. Meanwhile, NCT enhanced the infiltration of CD4+ GzmB+ T cells in the central region of the pMMR CRC, which was also identified as an independent protective factor of overall survival (OS) and DFS in NCT group.ConclusionWe demonstrated that the level of CD4+ GzmB+ T cells located in the center of tumor could provide great prognostic value for pMMR CRC patients. And the application of neoadjuvant chemotherapy further improves the infiltration of CD4+ GzmB+ T cells in the central compartment. Further studies into the application of CD4+ GzmB+ T cells in tumor immunotherapy are needed.

A correction to this paper has been published: https://doi.org/10.1007/s13238-021-00833-y