Interleukin-7 (IL-7) is a non-hematopoietic cell-derived cytokine with a central role in the adaptive immune system. It promotes lymphocyte development in the thymus and maintains survival of naive and memory T cell homeostasis in the periphery. Moreover, it is important for the organogenesis of lymph nodes (LN) and for the maintenance of activated T cells recruited into the secondary lymphoid organs (SLOs). The immune capacity of cancer patients is suppressed that is characterized by lower T cell counts, less effector immune cells infiltration, higher levels of exhausted effector cells and higher levels of immunosuppressive cytokines, such as transforming growth factor β (TGF-β). Recombinant human IL-7 (rhIL-7) is an ideal solution for the immune reconstitution of lymphopenia patients by promoting peripheral T cell expansion. Furthermore, it can antagonize the immunosuppressive network. In animal models, IL-7 has been proven to prolong the survival of tumor-bearing hosts. In this review, we will focus on the mechanism of action and applications of IL-7 in cancer immunotherapy and the potential restrictions for its usage.

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.

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.

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.