Gene Modification Strategies to Induce Tumor Immunity

The immune system provides an attractive option for use in cancer therapy. Our increasing understanding of the molecular events important in the generation of an effective immune response presents us with the opportunity to manipulate key genes to boost the immune response against cancer. Genetic modification is being employed to enhance a range of immune processes including antigen presentation, activation of specific T cells, and localization of immune effectors to tumors. In this review, we describe how many diverse cell types, including dendritic cells, T cells, and tumor cells, are being modified with a variety of genes, including those encoding antigens, cytokines, and chemokines, in order to enhance tumor immunity

Cancer immunoediting by the innate immune system in the absence of adaptive immunity

Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2, and RAG2x γc mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2x γc mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting

Stable IL-10: A New Therapeutic that Promotes Tumor Immunity

In this issue of Cancer Cell, Mumm et al. demonstrate that pegylated IL-10 increases CD8+ T cell numbers, IFN-γ secretion, and cytotoxicity in established tumors, enhancing antigen presentation machinery and suppressing tumor growth. This approach may enhance T cell immune responses in cancers with reduced T cell infiltration

Targeting immunosuppressive adenosine in cancer

Despite the success of anti-programmed cell death protein 1 (PD1), anti-PD1 ligand 1 (PDL1) and anti-cytotoxic T lymphocyte antigen 4 (CTLA4) therapies in advanced cancer, a considerable proportion of patients remain unresponsive to these treatments (known as innate resistance). In addition, one-third of patients relapse after initial response (known as adaptive resistance), which suggests that multiple non-redundant immunosuppressive mechanisms coexist within the tumour microenvironment. A major immunosuppressive mechanism is the adenosinergic pathway, which now represents an attractive new therapeutic target for cancer therapy. Activation of this pathway occurs within hypoxic tumours, where extracellular adenosine exerts local suppression through tumour-intrinsic and host-mediated mechanisms. Preclinical studies in mice with adenosine receptor antagonists and antibodies have reported favourable antitumour immune responses with some definition of the mechanism of action. Currently, agents targeting the adenosinergic pathway are undergoing first-in-human clinical trials as single agents and in combination with anti-PD1 or anti-PDL1 therapies. In this Review, we describe the complex interplay of adenosine and adenosine receptors in the development of primary tumours and metastases and discuss the merits of targeting one or more components that compose the adenosinergic pathway. We also review the early clinical data relating to therapeutic agents inhibiting the adenosinergic pathway

Biology and clinical observations of regulatory T cells in cancer immunology

This review specifically examines the role of regulatory T cells (Tregs) in cancer in both mice and the clinic. Due to the rapid refinement of the definition of Tregs and their heterogeneity, emphasis is given to research findings over the past three years. For clarity, this review is broadly divided into three short sections that outline the basic biology of Tregs - (1) Treg lineage and development, (2) Treg subsets, and (3) mechanisms of Treg-mediated immune suppression; followed by two more comprehensive sections that cover; (4) clinical observations of Tregs and cancer, and (5) modifications of Treg biology as cancer immunotherapies. The latter two sections discuss the measurement of function and frequency of Treg in model systems and clinical trials and possible ways to interfere with Treg-mediated immune suppression with the focus on recent pre-clinical and clinical findings

The interaction between murine melanoma and the immune system reveals that prolonged responses predispose for autoimmunity

An assessment of antitumor immunity versus autoimmunity as provoked by the specific depletion of FOXP3 Tregs is now possible with the development of Foxp3-diphtheria toxin receptor-like transgenic mouse models. We have used the poorly immunogenic B16F10 melanoma model to characterize a very heterogeneous antitumor effect of the immune response induced by Treg depletion. Depletion and neutralization studies demonstrated the importance of host T cells and interferon γ (IFNγ) in mediating the antitumor response developing in Treg-depleted mice. Such a response correlated with increased proliferation of granzyme B- and IFNγ-producing T cells in the tumor. Furthermore, enhanced antitumor immunity modulated the expression of MHC Class I molecules by B16F10 melanoma cells in Tregdepleted mice. Since Foxp3+ Treg depletion induced a significantly heterogeneous antitumor response, for the first time we were able to assess antitumor immunity and autoimmunity across different groups of responding mice. Strikingly, the duration of the tumor-immune system interaction provoked in individual Treg-depleted mice positively correlated with their propensity to develop vitiligo. A rapid complete tumor rejection was not associated with the development of autoimmunity, however, a proportion of mice that suppressed, but did not effectively clear, B16F10 melanoma did develop vitiligo. The significant implication is that approaches that combine with Treg depletion to rapidly reject tumors may also diminish autoimmune toxicities

Molecular pathways: targeting CD96 and TIGIT for cancer immunotherapy

The receptors CD96 and TIGIT are expressed on the surface of T and NK cells and recent studies suggest both play important inhibitory roles in immune function. CD96 has been shown to modulate immune cell activity in mice, with Cd96-/- mice displaying hypersensitive NK cell responses to immune challenge and significant tumor resistance. TIGIT overexpression has been shown to reduce NK cell-mediated cytotoxicity. TIGIT is also upregulated on T-cells during cancer and chronic viral infection, with expression associated with effector T-cell exhaustion and increased Treg suppression. The counterbalance between the putative inhibitory CD96, TIGIT receptors and the activating receptor, CD226, offers unique strategies for immuno-oncology drug development. Blocking CD96 or TIGIT with monoclonal antibodies (mAbs) has been shown to improve tumor control in mice, in particular when used in combination with PD-1/PD-L1 blockade. These results have highlighted these pathways as promising new targets for immune modulation. This review will examine the rationale behind targeting CD96 and TIGIT and discuss the potential approaches in translating these preclinical findings into novel clinical agents

The promise of neoadjuvant immunotherapy and surgery for cancer treatment

Cancer immunotherapies utilizing immune checkpoint inhibitors (ICI) have demonstrated durable efficacy in a proportion of patients with advanced/metastatic cancers. More recently, the use of ICIs for the adjuvant treatment of patients with surgically resectable melanoma has also demonstrated efficacy by improving relapse-free survival and in the case of ipilimumab (anti–CTLA-4) also improving overall survival. Although promising, the effective scheduling of surgery and immunotherapy and its duration is not well elucidated. Recent preclinical studies suggest that surgery followed by adjuvant therapy might be suboptimal as compared with an approach in which immunotherapy is applied before surgery (neoadjuvant immunotherapy). Encouraging findings from early-phase clinical trials in melanoma, non–small cell lung carcinoma, and glioblastoma support the idea that neoadjuvant immunotherapy might have improved clinical efficacy over an adjuvant application. In this review, we discuss the existing rationale for the use of neoadjuvant immunotherapy, its apparent strengths and weaknesses, and implications for the design of future clinical trials