Harnessing TH9 cells in cancer immunotherapy

CD4 T cell effector subsets not only profoundly affect cancer progression, but recent evidence also underscores their critical contribution to the anticancer efficacy of immune checkpoint inhibitors. In 2012, the two seminal studies suggested the superior antimelanoma activity of T_H9 cells over other T cell subsets upon adoptive T cell transfer. While these findings provided great impetus to investigate further the unique functions of T_H9 cells and explore their relevance in cancer immunotherapy, the following questions still remain outstanding: are T_H9 cell anticancer functions restricted to melanoma? What are the factors favouring T_H9 cell effector functions? What is the contribution of T_H9 cells to cancer immunotherapy treatments? Can T_H9 cells be identified in humans and, if so, what is their clinical relevance? By reviewing the studies addressing these questions, we will discuss how T_H9 cells could be therapeutically harnessed for cancer immunotherapy strategies.     

Cancer immunotherapy by targeting immune checkpoint receptors

The immune system plays a pivotal role in defending our body from invading pathogens and in surveillance against cancer. While most cells that acquire mutations are detected and destroyed by immunocytes, a small number of transformed cells succeed in evading immune destruction by inhibiting immune checkpoint regulatory pathways, leading to suppression of anti-cancer immune responses. Under normal conditions, immune checkpoint receptors maintain self-tolerance, prevent immunopathology, and regulate overall immune homeostasis. However, their skewed activation by cancer cells may lead to the suppression of nascent anti-tumor immunity and the promotion of tumor growth. Discovering the role of immune checkpoints in cancer and understanding their mode of operation has led to the development of novel strategies for cancer immunotherapy, which are based on the intervention or blockade of immune checkpoint-regulated pathways. Clinical studies have demonstrated that immune checkpoint co-inhibitory receptor-blocking antibodies can revert tumor-induced immunosuppression and augment overall anti-tumor immunity. These antibodies induced durable clinical responses and unprecedented therapeutic benefits in multiple types of malignancies. Although immune checkpoint inhibitors have revolutionized cancer therapy, the clinical benefits of these drugs have been limited to subsets of cancer patients and treatments frequently associated with a unique spectrum of toxicities, termed immune-related adverse events. Future discoveries of novel immune checkpoint receptors, identification of new prognostic and predictive biomarkers, and improvement of combination therapies are likely to boost the success rate of cancer immunotherapy and increase the survival rates of patients with different types of cancers.     

Breast cancer immunotherapy

Breast cancer is a leading cause of cancer-related deaths in women worldwide.Although tumorectomy,radiotherapy,chemotherapy and hormone replacement therapy have been used for the treatment of breastcancer,there is no effective therapy for patients with invasive and metastatic breast cancer.Immunotherapymay be proved effective in treating patients with advanced breast cancer.Breast cancer immunotherapyincludes antibody based immunotherapy,cancer vaccine immunotherapy,adoptive T cell transferimmunotherapy and T cell receptor gene transfer immunotherapy.Antibody based immunotherapy such as themonoclonal antibody against HER-2/neu (trastuzumab) is successfully used in the treatment of breast cancerpatients with over-expressed HER-2/neu,however,HER-2/neu is over-expressed only in 25-30% of breastcancer patients.Cancer vaccine immunotherapy is a promising method to treat cancer patients.Cancervaccines can be used to induce specific anti-tumor immunity in breast cancer patients,but cannot induceobjective tumor regression.Adoptive T cell transfer immunotherapy is an effective method in the treatment ofmelanoma patients.Recent advances in anti-tumor T cell generation ex vivo and limited clinical trial data havemade the feasibility of adoptive T cell transfer immunotherapy in the treatment of breast cancer patients.T cellreceptor gene transfer can redirect the specificity of T cells.Chimeric receptor,scFv(anti-HER-2/neu)/zetareceptor,was successfully used to redirect cytotoxic T lymphocyte hybridoma cells to obtain anti-HER-2/neupositive tumor cells,suggesting the feasibility of treatment of breast cancer patients with T cell receptor genetransfer immunotherapy.Clinical trials will approve that immunotherapy is an effective method to cure breastcancer disease in the near future.Cellular & Molecular Immunology.2004;1(4):247-255.     

Trispecific antibodies for cancer immunotherapy

Despite the clinical success of monoclonal and bispecific antibodies, there are still limitations in the therapeutic effect of malignant tumours, such as low response rate, treatment resistance, and so on, inspiring the exploration of trispecific antibodies (TsAbs). TsAbs further improve the safety and efficacy and has great clinical potential through three targets combination and formats optimization. This article reviews the development history and the target combination features of TsAbs. Although there are still great challenges in the clinical application of TsAbs, it is undeniable that TsAbs may be a breakthrough in the development of antibody drugs.     

Suppression of T cells by myeloid-derived suppressor cells in cancer

Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells defined by their immunosuppression. Elevated levels of certain soluble cytokines in tumor microenvironment, such as IL-6 and IL-10, contribute to the recruitment and accumulation of tumor-associated MDSCs. In turn, MDSCs secret IL-6 and IL-10 and form a positive self-feedback to promote self-expansion. MDSCs also release other soluble cytokines such as TGF-β and chemokines to exert their suppressive function by induction of regulatory T cells. Exhaustion of some amino acids by MDSCs with many secretory enzymes or membrane transporters as well as their metabolites leads to blockage of T cells development. The interaction of membrane molecules on MDSCs and T cells leads inactivation and apoptosis of T cells. There may be one or some dominant mechanism(s) by which MDSCs impair the immune system in different tumor microenvironment. Thus, it is important to identify the subpopulations of MDSCs and clarify the dominant mechanism(s) through which MDSCs inhibit antitumor immunity in order to establish a more individual immunotherapy by eliminating MDSCs-mediated suppression. Currently studies concentrated on therapeutic strategies targeting MDSCs have obtained promising results. However, more studies are needed to demonstrate their clinical safety and efficacy.     

Dendritic cells in cancer immunotherapy

DC initiate and regulate T‐cell immunity and are thus the key to optimization of all types of vaccines. Insights into DC biology offer many opportunities to enhance immunogenicity. In this Viewpoint, I discuss some recent developments and findings that are of immediate relevance for the clinical development of cancer vaccines. In addition, I emphasize my personal view that we should explore the potential of adoptively transferred DC (i.e. DC vaccination) as cancer vaccines by performing two‐armed trials that address critical variables and by delivering antigens via mRNA‐transfected DC.     

The molecular basis of cancer immunotherapy by cytotoxic T lymphocytes

 The disappointing clinical results of cancer immunotherapy of the past few decades have not diminished the optimism about the potential of the new generation of immunotherapeutic strategies towards treatment of malignant disease. Tremendous progress has been made over recent years in unveiling the molecular basis of antigen presentation and recognition by cytotoxic T lymphocytes (CTL). The molecular concepts that have emerged from these studies have led to the design of novel anticancer vaccines and CTL-based immunotherapeutics. This review is to highlight the current molecular insights of antigen presentation and CTL recognition/activation, and their impact on the rational design of therapeutic interventions that may result in protective, CTL-based antitumor immunity. Received: 21 February 1997 / Accepted: 7 May 1997     

Cancer immunotherapy: dawn of the death of cancer?

Abstract

Cancer is one of the proficient evaders of the immune system which claims millions of lives every year. Developing therapeutics against cancer is extremely challenging as cancer involves aberrations in self, most of which are not detected by the immune system. Conventional therapeutics like chemotherapy, radiotherapy are not only toxic but they significantly lower the quality of life. Immunotherapy, which gained momentum in the 20^th century, is emerging as one of the alternatives to the conventional therapies and is relatively less harmful but more costly. This review explores the modern advances in an array of such therapies and try to compare them along with a limited analysis of concerns associated with them.     

CRISPR/Cas9 and CAR-T cell,collaboration of two revolutionary technologies in cancer immunotherapy,an instruction for successful cancer treatment

Clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease9 (CRISPR/Cas9) technology, an acquired immune system in bacteria and archaea, has provided a new tool for accurately genome editing. Using only a single nuclease protein in complex with 2 short RNA as a site-specific endonuclease made it a simple and flexible genome editing tool to target nearly any genomic locus. Due to recent developments in therapeutic engineered T cell and effective responses of CD19-directed chimeric antigen receptor T cells (CART19) in patients with B-cell leukemia and lymphoma, adoptive T cell immunotherapy, particularly CAR-T cell therapy became a rapidly growing field in cancer therapy and recently Kymriah and Yescarta (CD19-directed CAR-T cells) were approved by FDA. Therefore, the combination of CRISPR/Cas9 technology as a genome engineering tool and CAR-T cell therapy (engineered T cells that express chimeric antigen receptors) may lead to further improvement in efficiency and safety of CAR-T cells. This article reviews mechanism and therapeutic application of CRISPR/Cas9 technology, accuracy of this technology, cancer immunotherapy by CAR T cells, the application of CRISPR technology for the production of universal CAR T cells, improving their antitumor efficacy, and biotech companies that invested in CRISPR technology for CAR-T cell therapy.     

Molecular insights into the development of T cell-based immunotherapy for prostate cancer

Using a patient’s own immune system to fight cancer is a highly active area of cancer research. Four years ago, sipuleucel-T became the first approved cancer vaccine, which was developed to enhance T-cell immunity against metastatic castration-resistant prostate cancer. Other prostate cancer vaccines, including a viral-based vaccine PROSTVAC-VF and a cellular vaccine GVAX, are in development. Moreover, several clinical trials are investigating the role of immune checkpoint blockade in the treatment of prostate cancer. Ipilimumab and nivolumab are potent T cell checkpoint inhibitors that reverse immunologic tolerance in multiple types of cancers. Here we discuss the mechanisms underlying antitumor T cell responses as well as the development of immunotherapies for prostate cancer.     

Exploiting scavenger receptors in cancer immunotherapy: Lessons from CD5 and SR‐B1

Scavenger receptors (SRs) are structurally heterogeneous cell surface receptors characterized by their capacity to remove extraneous or modified self‐macromolecules from circulation, thus avoiding the accumulation of noxious agents in the extracellular space. This scavenging activity makes SRs important molecules for host defense and homeostasis. In turn, SRs keep the activation of the steady‐state immune response in check, and participate as co‐receptors in the priming of the effector immune responses when the macromolecules are associated with a threat that might compromise host homeostasis. Therefore, SRs built up sophisticated sensor mechanisms controlling the immune system, which may be exploited to develop novel drugs for cancer immunotherapy. In this review, we focus on the regulation of the anti‐tumor immune response by two paradigmatic SRs: the lymphocyte receptor CD5 and the more broadly distributed scavenger receptor class B type 1 (SR‐B1). Cancer immunity can be boosted by blockade of SRs working as immune checkpoint inhibitors (CD5) and/or by proper engagement of SRs working as innate danger receptor (SR‐B1). Thus, these receptors illustrate both the complexity of targeting SRs in cancer immunotherapy and also the opportunities offered by such an approach.     

Adoptive immunotherapy for cancer

Recent clinical success has underscored the potential for immunotherapy based on the adoptive cell transfer (ACT) of engineered T lymphocytes to mediate dramatic, potent, and durable clinical responses. This success has led to the broader evaluation of engineered T-lymphocyte-based adoptive cell therapy to treat a broad range of malignancies. In this review, we summarize concepts, successes, and challenges for the broader development of this promising field, focusing principally on lessons gleaned from immunological principles and clinical thought. We present ACT in the context of integrating T-cell and tumor biology and the broader systemic immune response.     

Natural killer cell engagers in cancer immunotherapy: Next generation of immuno-oncology treatments

Immuno-oncology is revolutionizing the treatment of cancers, by inducing the recognition and elimination of tumor cells by the immune system. Recent advances have focused on generating or unleashing tumor antigen-specific T-cell responses, leading to alternative treatment paradigms for many cancers. Despite these successes, the clinical benefit has been limited to a subset of patients and certain tumor types, highlighting the need for alternative strategies. One innovative approach is to broaden and amplify antitumoral immune responses by targeting innate immunity. Particularly, the aim has been to develop new antibody formats capable of stimulating the antitumor activity of innate immune cells, boosting not only their direct role in tumor elimination, but also their function in eliciting multicellular immune responses ultimately resulting in long-lasting tumor control by adaptive immunity. This review covers the development of a new class of synthetic molecules, natural killer cell engagers (NKCEs), which are built from fragments of monoclonal antibodies (mAbs) and are designed to harness the immune functions of NK cells in cancer. As currently shown in preclinical studies and clinical trials, NKCEs are promising candidates for the next generation of tumor immunotherapies.     

Dextran derivative-based pH-sensitive liposomes for cancer immunotherapy

pH-Sensitive dextran derivatives having 3-methylglutarylated residues (MGlu-Dex) were prepared by reacting dextran with 3-methyl-glutaric anhydride. MGlu-Dex changed the protonation state and their characteristics from hydrophilic to hydrophobic in neutral and acidic pH regions. Surface modification of egg yolk phosphatidylcholine liposomes with MGlu-Dex produced highly pH-sensitive liposomes that were stable at neutral pH but which were destabilized strongly in the weakly acidic pH region. MGlu-Dex-modified liposomes were taken up efficiently by dendritic cells and delivered entrapped ovalbumin (OVA) molecules into the cytosol. When MGlu-Dex-modified liposomes loaded with OVA were administered subcutaneously to mice, the antigen-specific humoral and cellular immunity was induced more effectively than the unmodified liposomes loaded with OVA. Furthermore, administration of MGlu-Dex-modified liposomes loaded with OVA to mice bearing E.G7-OVA tumor significantly suppressed tumor growth and extended the mice survival. Results suggest that MGlu-Dex-modified liposomes are promising for the production of safe and potent antigen delivery systems that contribute to the establishment of efficient cancer immunotherapy.     

T细胞受体基因转染过继性免疫治疗的研究进展

利用T细胞进行过继性免疫治疗是治疗病毒感染性疾病和肿瘤的理想方法,但是用于治疗的T细胞的特异性、亲和性和数量等限制了其应用,如何获得特异、高效、一定数量的T细胞是目前亟待解决的问题。采用TCR基因转染的方法,将特异性高亲和力TCR转移到受体的T细胞中,可以特异性杀伤受体体内的肿瘤细胞。     

Cancer immunotherapy: A need for peripheral immunodynamic monitoring

Immunotherapy has become an important approach for treating different tumours which has shown significant efficacy in numerous clinical trials, especially those using new checkpoint inhibitors and adoptive cell therapy, which have rapidly become widespread after being approved. However, analysis of peripheral immune biomarkers before and after immunotherapy and their relationship to clinical responses and disease prognosis have rarely been performed in clinical trials. In this review, we examine dynamic changes in the immune system before and after therapy by analyzing recent clinical trials of immunotherapy in patients with cancer that focused on checkpoint inhibitors and adoptive cell therapy. Our aim was to identify circulating biomarkers which can specifically predict clinical response and prognosis, as well as toxicities of immunotherapy. Through this approach, we hope to advance our understanding of the mechanisms of immunotherapy with the goal of developing individualized treatment for cancer patients.     

Pyroptosis: A road to next-generation cancer immunotherapy

The goal of cancer immunotherapy is to clear tumor cells by activating antitumor immunity, especially by mobilizing tumor-reactive CD8⁺T cells. Pyroptosis, programmed lytic cell death mediated by gasdermin (GSDM), results in the release of cellular antigens, damage-associated molecular patterns (DAMPs) and cytokines. Therefore, pyroptotic tumor cell-derived tumor antigens and DAMPs not only reverse immunosuppression of the tumor microenvironment (TME) but also enhance tumor antigen presentation by dendritic cells, leading to robust antitumor immunity. Exploring nanoparticles and other approaches to spatiotemporally control tumor pyroptosis by regulating gasdermin expression and activation is promising for next-generation immunotherapy.     

Role of miRNAs in immune responses and immunotherapy in cancer

In the past decade, the study of mechanisms of cancer immunity has seen a prominent boom, which paralleled the increased amount of research on the clinical efficacy of immune checkpoint blockade in several lethal types of cancers. This conspicuous effort has led to the development of successful immunotherapy treatment strategies, whose medical impact has been recognized by the awarding of 2018 Nobel Prize in Physiology or Medicine to the two pioneers of check point inhibitor research, Tasuku Honjo and James Allison. Despite these promising achievements, the differences in the clinical response rate in different cancer patients and the high risk of toxicity of immune‐based therapies represent crucial challenges. More remarkably, the causes responsible for different outcome (success vs failure) in patients with tumor having same histotype and clinical characteristics remain mostly unknown. MicroRNAs (miRNAs), small regulatory noncoding RNA molecules representing the most studied component of the dark matter of the human genome, are involved in the regulation of many pathways of cancer and immune cells. Therefore, understanding the role of miRNAs in controlling cancer immunity is necessary, as it can contribute to reveal mechanisms that can be modulated to improve the success of immunetherapy in cancer patients. Here, we discuss the latest findings on immune pathways regulated by miRNAs in cancer, miRNA‐mediated regulation of immune cells in the tumor microenvironment, and miRNAs as potential target for immunotherapies.     

Therapy implications of the role of interleukin-2 in cancer

Introduction: Despite its apparent failure in cancer therapy, IL-2 still remains fundamental in the activation of antitumor immunity.

Areas covered: The aim of this review is the reinterpretation of the role of IL-2 in anticancer immunity, according to knowledge gained of the cytokine network, by highlighting its importance in inducing T helper-1 (TH1) cell proliferation, natural killer (NK) actHivation and IL-12 secretion. However, its main negative effect is the stimulation of regulatory T cells (Tregs), which in contrast suppresses anticancer immunity.

Expert commentary: Cardiovascular toxicity, which was the main clinical problem at the beginning of IL-2 therapy at high intravenous doses, has almost been completely solved by subcutaneous low-dose IL-2 injection. In order to enhance the anticancer efficacy of IL-2, several strategies have been explored, including chemotherapy and interferon, but up until now no regimen has appeared to be clearly better than IL-2 alone. However, considering the role of immune checkpoints (PD-1 and CTLA-4) in Tregs stimulation, the most effective immunotherapy in the future could be concomitant IL-2 administration, to enhance lymphocyte count, and checkpoint inhibitors, such as anti-PD1 or anti-CTLA-4 monoclonal antibodies, or IL-12, which is also able to counteract IL-2-induced Treg cell generation. Therefore, the time for IL-2 immunotherapy in cancer treatment has finally arrived.