Jianbao Gao

Complement aids in the construction of an immunosuppressive tumor microenvironment. Tumor cell–derived C3 has been previously reported, but whether and how it acts on antitumor immunity remains to be elucidated. Here, we describe a mechanism for tumor cell–derived C3 in suppressing antitumor immunity. Tumor cell–derived C3 was activated intracellularly, which results in generation of C3a. C3a modulated tumor-associated macrophages via C3a-C3aR-PI3Kγ signaling, thereby repressing antitumor immunity. Deletion of C3 in tumor cells that had high C3 expression enhanced efficacy of anti–PD-L1 treatment. Collectively, our results suggest tumor cell–derived C3 may be a useful target for cancer immunotherapy and that targeting C3 in tumor cells may enhance antitumor immunity.

6 figures and 1 table are included

Complement aids in the construction of an immunosuppressive tumor microenvironment. Tumor cell–derived C3 has been previously reported, but whether and how it acts on antitumor immunity remains to be elucidated. Here, we describe a mechanism for tumor cell–derived C3 in suppressing antitumor immunity. Tumor cell–derived C3 was activated intracellularly, which results in generation of C3a. C3a modulated tumor-associated macrophages via C3a-C3aR-PI3Kγ signaling, thereby repressing antitumor immunity. Deletion of C3 in tumor cells that had high C3 expression enhanced efficacy of anti–PD-L1 treatment. Collectively, our results suggest tumor cell–derived C3 may be a useful target for cancer immunotherapy and that targeting C3 in tumor cells may enhance antitumor immunity.

6 figures and 1 table are included

Anti–PD-1/PD-L1 therapy, either by anti–PD-1 antibody or anti–PD-L1 antibody, has efficacy by reinvigorating tumor-infiltrating CD8 ⁺ T cells in a subset of patients with cancer, but it has unequal effects on heterogeneous CD8 ⁺ T cell populations. Hence, the subset crucial to efficacious PD-1 blockade therapy remains elusive. Here, we found an increase in tumor-infiltrating CD200 ⁺ cytotoxic T lymphocytes (CTLs) upon PD-1/PD-L1 blockade, with higher proportions of CD200 ⁺ T cells positively related to a favorable clinical outcome to anti–PD-1/PD-L1 therapy in three independent cohorts of patients with cancer. Using multiple mouse tumor models, we demonstrated that CD200 ⁺ CTLs are essential for efficacious anti–PD-L1 therapy. Mechanistically, we observed a unique chromatin landscape in CD200 ⁺ CTLs and found that these cells are enriched for tumor antigen–specific CTLs and have antitumor effector functions. Coinoculation of CD200 ⁺ CTLs with tumor cells led to robust tumor regression in two transplanted mouse models. Clinically, we found that infiltration of CD200 ⁺ CTLs into tumors could predict immunotherapy efficacy in six patient cohorts. Together, our findings reveal that CD200 ⁺ CTLs in the tumor microenvironment are crucial for efficacious anti–PD-1/PD-L1 therapy and could serve as a predictor of successful immunotherapy in the clinic.

Epigenetic modifications to histones dictate the differentiation of naïve CD4⁺ T cells into different subsets of effector T helper (T_H) cells. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the mechanism regulating the differentiation of T_H1, T_H2 and regulatory T (T_reg) cells. However, whether and how EZH2 regulates follicular helper T (T_FH) cell differentiation remain unknown. Using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection, we observed abundant EZH2 expression and associated H3K27me3 modifications preferentially in the early committed virus-specific T_FH cells compared to those in T_H1 cells. Ablation of EZH2 in LCMV-specific CD4⁺ T cells leads to a selective impairment of early T_FH cell fate commitment, but not late T_FH differentiation or memory T_FH maintenance. Mechanistically, EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for T_FH fate commitment, particularly B cell lymphoma 6 (Bcl6), and thus directs T_FH cell commitment. Therefore, we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early T_FH differentiation during acute viral infection.

Complement aids in the construction of an immunosuppressive tumor microenvironment. Tumor cell–derived C3 has been previously reported, but whether and how it acts on antitumor immunity remains to be elucidated. Here, we describe a mechanism for tumor cell–derived C3 in suppressing antitumor immunity. Tumor cell–derived C3 was activated intracellularly, which results in generation of C3a. C3a modulated tumor-associated macrophages via C3a-C3aR-PI3Kγ signaling, thereby repressing antitumor immunity. Deletion of C3 in tumor cells that had high C3 expression enhanced efficacy of anti–PD-L1 treatment. Collectively, our results suggest tumor cell–derived C3 may be a useful target for cancer immunotherapy and that targeting C3 in tumor cells may enhance antitumor immunity.

Purpose: Centromere protein U (CENPU) abnormally exhibits high expression in various types of human tumor tissues and participates in tumor progression; however, its expression pattern and biological function in lung cancer have not yet been elucidated. In the present study, we explored the clinical significance and biological function of CENPU in lung cancer. Materials and methods: The Cancer Genome Atlas (TCGA) data analyses, quantitative real-time PCR (RT-PCR), and Western blotting were performed to quantify CENPU and FOXM1 expression in non-small-cell lung cancer (NSCLC) samples. Survival data were obtained from Kaplan–Meier plotter or PROGgene V2 prognostic database. The function of CENPU in lung cancer cell proliferation was determined using 5-ethynyl-2′-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and cell cycle assays, and the underlying mechanism was determined through bioinformatic analyses and validated by in vitro siRNA or plasmid transfection experiments. Results: CENPU was abnormally overexpressed in NSCLC samples compared with matched paired normal tissues. Higher expression of CENPU predicted worse overall survival (OS) and relapse-free survival (RFS) in NSCLC patients. Knockdown of CENPU expression by siRNA significantly inhibited proliferation and delayed cell cycle progression of lung cancer cells. To figure out the mechanism, bioinformatic analyses were performed and the results showed that the transcription factor, FOXM1, positively correlated with CENPU. Further in vitro experiments indicated that FOXM1 was the possible downstream transcription factor of CENPU as the knockdown of CENPU led to lower expression of FOXM1 and the overexpression of FOXM1 significantly reversed the inhibition of proliferation caused by CENPU knockdown. Furthermore, FOXM1 was highly expressed in NSCLC. The knockdown of FOXM1 also attenuated proliferation and induced G1 arrest in lung cancer cells. Conclusion: CENPU was highly expressed in NSCLC tissues, wherein it promoted lung cancer cell proliferation via the transcription factor, FOXM1, which could be a potential target for therapeutic strategies.

Impaired immunity in patients with late-stage cancer is not limited to antitumor responses, as demonstrated by poor vaccination protection and high susceptibility to infection^1,2,3. This has been largely attributed to chemotherapy-induced impairment of innate immunity, such as neutropenia², whereas systemic effects of tumors on hematopoiesis and adoptive immunity remain incompletely understood. Here we observed anemia associated with severe deficiency of CD8⁺ T cell responses against pathogens in treatment-naive mice bearing large tumors. Specifically, we identify CD45⁺ erythroid progenitor cells (CD71⁺TER119⁺; EPCs) as robust immunosuppressors. CD45⁺ EPCs, induced by tumor growth–associated extramedullary hematopoiesis, accumulate in the spleen to become a major population, outnumbering regulatory T cells (T_regs) and myeloid-derived suppressor cells (MDSCs). The CD45⁺ EPC transcriptome closely resembles that of MDSCs, and, like MDSCs, reactive oxygen species production is a major mechanism underlying CD45⁺ EPC–mediated immunosuppression. Similarly, an immunosuppressive CD45⁺ EPC population was detected in patients with cancer who have anemia. These findings identify a major population of immunosuppressive cells that likely contributes to the impaired T cell responses commonly observed in patients with advanced cancer.