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The question as to why some hosts can eradicate their tumors while others succumb to tumor-progression remains unanswered. Here, a provocative concept is proposed that intrinsic differences in the T cell receptor (TCR) repertoire of individuals may influence the outcome of anti-tumor immunity by affecting the frequency and/or variety of tumor-reactive CD8 and/or CD4 tumor-infiltrating lymphocytes. This idea implicates that the TCR repertoire in a given patient might not provide sufficiently different TCR clones that can recognize tumor antigens, namely, “a hole in the TCR repertoire” might exist. This idea may provide a novel perspective to further dissect the mechanisms underlying heterogeneous anti-tumor immune responses in different hosts. Besides tumor-intrinsic heterogeneity and host microbiome, the various factors that may constantly shape the dynamic TCR repertoire are also discussed. Elucidating mechanistic differences in different individuals’ immune systems will allow to better harness immune system to design new personalized cancer immunotherapy.

The successful implementation of immunotherapies has provided new impetus in the fight against cancer. Antibody-mediated blockade of immune checkpoint molecules PD-1/PD-L1 and CTLA-4 has had a dramatic impact upon the treatment of previously intractable cancers such as malignant melanoma, while adoptive cell therapies using chimeric antigen receptor-bearing T cells have proven highly efficacious in B cell leukemia. Furthermore, significant progress has been made in understanding the mechanisms by which tumors evade or become resistant to these immunotherapies. In this regard, approaches to broaden the applicability and enhance the efficacy of immunotherapies increasingly include modulation of tumor and immune cell metabolism. In this mini-review, we highlight the most recent studies describing novel approaches and targets for the manipulation of the tumor microenvironment and T cell metabolism and describe how these approaches are being combined with current immunotherapies in preclinical studies.

Foxp3-expressing regulatory T (Treg) cells, which are indispensable for preventing autoimmunity, also suppress effective tumor immunity. Treg cells abundantly infiltrate into tumor tissues, which is often associated with poor prognosis in cancer patients. Removal of Treg cells enhances anti-tumor immune responses but may also elicit autoimmunity. A key issue in devising Treg-targeting cancer immunotherapy is, therefore, how to specifically deplete Treg cells infiltrating into tumor tissues without affecting tumor-reactive effector T cells, while suppressing autoimmunity. This can be achieved by differentially controlling Treg and effector T cells by various ways. In this review, we discuss how tumor-infiltrating Foxp3⁺ Treg cells hamper effective anti-tumor immune responses especially in tumor tissues and how they can be specifically targeted for augmenting tumor immunity but not autoimmunity.

The pervasive use of therapeutic antibodies targeting programmed cell death protein 1 (PD-1) to boost anti-tumor immunity has positioned this approach to become the standard-of-care for some solid tumor malignancies. However, little is known as to how blockade of PD-1 may alter the function or phenotype of tumor-infiltrating lymphocytes (TIL). We used our ongoing Phase II clinical trial of pembrolizumab for patients with rare solid tumors from various types (NCT02721732) with matched core biopsies taken at baseline and after initial dose of anti-PD-1 (15–21 days post-dose) to elucidate this question. One fresh core needle biopsy was used to propagate TIL ex vivo to analyze phenotype and function using flow cytometry in both CD8⁺ and CD4⁺ TIL populations. An enriched CTLA-4 expression in the CD4⁺ TIL population was observed in TIL expanded from the on-treatment samples compared to TIL expanded from the matched baseline (n = 22, p = 0.0007) but was not observed in patients who experienced tumor regression. Impact on functionality was evaluated by measuring secretion of 65 soluble factors by expanded TIL from 26 patients at baseline and on-treatment. The CD8⁺ TIL population demonstrated a diminished cytokine secretion profile post-pembrolizumab. Overall, our study assesses the ramifications of one dose of anti-PD-1 on TIL in rare solid tumor types.

Introduction of Chimeric Antigen Receptors to NK cells has so far been the main practical method for targeting NK cells to specific surface antigens. In contrast, T cell receptor (TCR) gene delivery can supply large populations of cytotoxic T-lymphocytes (CTL) targeted against intracellular antigens. However, a major barrier in the development of safe CTL-TCR therapies exists, wherein the mispairing of endogenous and genetically transferred TCR subunits leads to formation of TCRs with off-target specificity. To overcome this and enable specific intracellular antigen targeting, we have tested the use of NK cells for TCR gene transfer to human cells. Our results show that ectopic expression of TCR α/β chains, along with CD3 subunits, enables the functional expression of an antigen-specific TCR complex on NK cell lines NK-92 and YTS, demonstrated by using a TCR against the HLA-A2-restricted tyrosinase-derived melanoma epitope, Tyr_368-377. Most importantly, the introduction of a TCR complex to NK cell lines enables MHC-restricted, antigen-specific killing of tumor cells both in vitro and in vivo. Targeting of NK cells via TCR gene delivery stands out as a novel tool in the field of adoptive immunotherapy which can also overcome the major hurdle of “mispairing” in TCR gene therapy.

Macrophage plasticity is the ability of mononuclear phagocytes to change phenotype, function, and genetic reprogramming upon encounter of specific local stimuli. In the tumor microenvironment, Tumor-Associated Macrophages (TAMs) acquire an immune-suppressive and tumor-promoting phenotype. With the aim to re-educate TAMs to antitumor effectors, in this study, we used two immunestimulatory compounds: the TLR7 agonist Imiquimod (IMQ) and the TLR3 agonist Poly(I:C). To better mimic in vitro the response of TAMs, we used Tumor-Conditioned Macrophages (TC-Mϕ) differentiated in the presence of tumor cell supernatants. Our results show that TC-Mϕ respond differently from conventional M2-polarized macrophages. Upon stimulation with IMQ, TC-Mϕ did not upregulate major histocompatibility complex (MHC II) molecules and unexpectedly expressed increased CD206. With both compounds, TC-Mϕ produced higher levels of inflammatory cytokines than M2 macrophages. IMQ and Poly(I:C) differed in the types of regulated genes and secreted mediators. Reflecting their signaling pathways, only IMQ significantly induced IL-1β and IL-6, while only Poly(I:C) stimulated CXCL10, and both upregulated CCL5. Of note, using a novel cytotoxicity assay, Poly(I:C), but not IMQ, was effective in triggering the cytotoxic activity of TC-Mϕ against cancer cells. Overall, the results demonstrate that Poly(I:C) stimulation of TC-Mϕ is superior than IMQ in terms of macrophage re-education toward antitumor effectors.

Dissecting the different steps of the processing and presentation of tumor-associated antigens is a key aspect of immunotherapies enabling to tackle the immune response evasion attempts of cancer cells. The immunodominant glycoprotein gp100_209-217 epitope, which is liberated from the melanoma differentiation antigen gp100^PMEL17, is part of immunotherapy trials. By analyzing different human melanoma cell lines, we here demonstrate that a pool of N-terminal extended peptides sharing the common minimal epitope is generated by melanoma proteasome subtypes. In vitro and in cellulo experiments indicate that ER-resident aminopeptidase 1 (ERAP1)—but not ERAP2—defines the processing of this peptide pool thereby modulating the T-cell recognition of melanoma cells. By combining the outcomes of our studies and others, we can sketch the complex processing and endogenous presentation pathway of the gp100_209-217-containing epitope/peptides, which are produced by proteasomes and are translocated to the vesicular compartment through different pathways, where the precursor peptides that reach the endoplasmic reticulum are further processed by ERAP1. The latter step enhances the activation of epitope-specific T lymphocytes, which might be a target to improve the efficiency of anti-melanoma immunotherapy.

It is well established that therapeutic impairment of Foxp3⁺ Treg in mice and humans favors immune rejection of solid tumors. Less explored is the impact Foxp3 allelic variants may have on tumor incidence, progression and therapy. In this work, we tested and demonstrate that the Foxp3^fgfp reporter allele, found previously to either enhance or reduce Treg function in specific autoimmunity settings, confers increased anti-tumor immunity. Our conclusions stem out of the analysis of three tumor models of different tissue origin, in two murine genetic backgrounds. When compared to wild type animals, mice carrying the Foxp3^fgfp allele spontaneously delay, reduce or prevent primary tumor growth, decrease metastasis growth, and potentiate the response to anti-CTLA4 monotherapy. These findings suggest allelic variances at the Foxp3 locus may serve as predictive indicators for personalized therapy and prognostics, and point at possible new therapeutic targets.

Overcoming the immunosuppressive tumor microenvironment (TME) is critical to realizing the potential of cancer immunotherapy strategies. Agonists of stimulator of interferon genes (STING), a cytosolic immune adaptor protein, have been shown to induce potent antitumor activity when delivered into the TME. However, the anionic properties of STING agonists make them poorly membrane permeable, and limit their ability to engage STING in the cytosol of responding cells. In this study, cationic liposomes with varying surface polyethylene glycol levels are used to encapsulate 2′3′ cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) to facilitate its cytosolic delivery. In vitro studies with antigen-presenting cells (APCs) revealed that liposomal formulations substantially improve the cellular uptake of cGAMP and proinflammatory gene induction relative to free drug. Liposomal encapsulation allows cGAMP delivery to metastatic melanoma tumors in the lung, leading to antitumor activity, whereas free drug produces no effect at the same dose. Injection of liposomal cGAMP into orthotopic melanoma tumors shows retention of cGAMP at the tumor site and colocalization with tumor-associated APCs. Liposomal delivery induces regression of injected tumors and produces immunological memory that protects previously treated mice from rechallenge with tumor cells. These results show that liposomal delivery improves STING agonist activity, and could improve their utility in clinical oncology.

Cancer vaccines, which have been widely investigated in the past few decades, are one of the most attractive strategies for cancer immunotherapy. Through the precise delivery of antigens and adjuvants to lymphoid organs or lymphocytes via nanotechnology, innate and adaptive immunity can be boosted to prevent the growth and relapse of malignant tumors. Indeed, nanomedicine offers great opportunities to improve the efficiency of vaccines. Various functional platforms are used to deliver small molecules, peptides, nucleic acids, and even whole cell antigens to the target area of interest, achieving enhanced antitumor immunity and durable therapeutic benefits. Herein, the recent progress in cancer vaccines based on nanotechnology is summarized. Novel platforms used for delivering tumor antigens, promoting adjuvant functions, and combining other therapeutic strategies are discussed. Moreover, possible striving directions and major challenges of nanomedicine for vaccination are also reviewed.

Lymph node (LN) metastasis causes poor prognosis for patients with prostate cancer (PCa). Although LN-cells and cellular responses play a pivotal role in cancer metastasis, the interplay between LN-cells and PCa cells is undetermined due to the small size and widespread distribution of LNs. To identify factors responsible for LN metastasis, a 3D cell culture biosystem is fabricated to simulate LN responses during metastasis. First, it is determined that LN explants previously exposed to high metastatic PCa release substantially more chemotactic factors to promote metastatic PCa migration than those exposed to low-metastatic PCa. Furthermore, T-lymphocytes are found to produce chemotactic factors in LNs, among which, CXCL12, CCL21, and IL-10 are identified to have the most chemotactic effect. To mimic the LN microenvironment, Cytodex beads are seeded with T cells to produce a LN-mimetic biosystem in both static and flow conditions. As expected, the flow condition permits prolonged cellular responses. Interestingly, when PCa cells with varying metastatic potentials are introduced into the system, it produces PCa-specific chemokines accordingly. These results support that the LN mimetic helps in analyzing the processes underlying metastasized LNs and for testing various treatments to reduce cancer LN metastasis.

Tumor-associated macrophages (TAMs) are of great interest in cancer immunology as they play an important role in the tumor microenvironment as cancer stromal cells recruited from circulating monocytes. TAMs are closely associated with tumor progression, including initiation, trophic growth, metabolism, angiogenesis, and metastasis; moreover, in clinical practice, their quantity can be related to poor prognosis. Fundamental and translational studies imply that TAMs are one of the most promising targets in tumor therapy. Herein, the biological origination and classification of TAMs, which correspond to their functions and differentiations, are reviewed in detail. In addition, recent basic research and clinical preprocess of TAMs in tumor immunotherapy are also discussed. Finally, the advances in the use of nanotechnology and TAMs for tumor therapy are discussed. This review focuses on the background and status of basic research and clinical significance of TAMs, points out the potential of TAMs in tumor immunological therapy, and clarifies the possibility of translation TAM-targeting therapies in medicine.

It is currently understood that in order for a tumor to successfully grow, it must evolve means of evading immune surveillance. In the past several decades, researchers have leveraged increases in the knowledge of tumor immunology to develop therapies capable of augmenting endogenous immunity and eliciting strong antitumor responses. In particular, the goal of anticancer vaccination is to train the immune system to properly utilize its own resources in the fight against cancer. Although attractive in principle, there are currently only limited examples of anticancer vaccines that are successfully translated to the clinic. Recently, there has been a significant push toward the use of nanotechnology for designing vaccine candidates that exhibit enhanced potency and specificity. Here, the recent developments in the field of anticancer nanovaccines are discussed. By taking advantage of the flexibility offered by nanomedicine to purposefully program immune responses, this new generation of vaccines has the potential to address many of the hurdles facing traditional platforms. A specific emphasis is placed on the emergence of cell membrane–coated nanoparticles, a novel biomimetic platform that can be used to generate personalized nanovaccines that elicit strong, multiantigenic antitumor responses.

Alum exhibits the superior biocompatibility in the history of human healthcare, as the only FDA-approved inorganic adjuvant in most human vaccines. However, up to now, there are few reports about the in-depth research between its nanostructure and carrier properties in vitro and in vivo. In this study, the caged architecture of uniform mesoporous γ-AlOOH nanorods (MANRs) comprises realigned pores and open windows at the edges, 1D tubular tunnels, and oxyhydroxide layer that can serve as carriers for cancer immunotherapy. Compared with commercial alum, the MANRs exhibit a higher loading amount of a model cancer antigen and a stronger intracellular uptake by THP-1-differentiated macrophage-like cells in vitro. Compared with commercial alum and soluble ovalbumin, the MANRs loaded with a model cancer antigen, ovalbumi, and an immunopotentiator, double-stranded RNA analog poly(I:C) markedly increase the anticancer immunity and CD4+ and CD8+ T cell populations in mouse splenocytes in vivo. The MANRs are promising as an adjuvant substance in cancer immunotherapy for clinical use.

The past few decades have witnessed the booming field of cancer immunotherapy. Cancer therapeutic vaccines, either alone or in combination with other immunotherapies such as adoptive cell therapy or immune checkpoint blockade therapy, are an attractive class of cancer immunotherapeutics. However, cancer vaccines have thus far shown suboptimal efficacy in the clinic. Nanomedicines offer unique opportunities to improve the efficacy of these vaccines. A variety of nanoplatforms have been investigated to deliver molecular or cellular or subcellular vaccines to target lymphoid tissues and cells, thereby promoting the potency and durability of anti-tumor immunity while reducing adverse side effects. In this article, we reviewed the key parameters and features of nanovaccines for cancer immunotherapy; we highlighted recent advances in the development of cancer nanovaccines based on synthetic nanocarriers, biogenic nanocarriers, as well as semi-biogenic nanocarriers; and we summarized newly emerging types of nanovaccines, such as those based on stimulator of interferon genes agonists, cancer neoantigens, mRNA vaccines, as well as artificial antigen-presenting cells.

This article is categorized under:

• Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Various cancer therapies have advanced remarkably over the past decade. Unlike the direct therapeutic targeting of tumor cells, cancer immunotherapy is a new strategy that boosts the host's immune system to detect specific cancer cells for efficient elimination. Nanoparticles incorporating immunomodulatory agents can activate immune cells and modulate the tumor microenvironment to enhance antitumor immunity. Such nanoparticle-based cancer immunotherapies have received considerable attention and have been extensively studied in recent years. This review thus focuses on nanoparticle-based platforms (especially naturally derived nanoparticles and synthetic nanoparticles) utilized in recent advances; summarizes delivery systems that incorporate various immune-modulating agents, including peptides and nucleic acids, immune checkpoint inhibitors, and other small immunostimulating agents; and introduces combinational cancer immunotherapy with nanoparticles, especially nanoparticle-based photo-immunotherapy and nanoparticle-based chemo-immunotherapy. Undoubtedly, the recent studies introduced in this review prove that nanoparticle-incorporated cancer immunotherapy is a highly promising treatment modality for patients with cancer. Nonetheless further research is needed to solve safety concerns and improve efficacy of nanoplatform-based cancer immunotherapy for future clinical application.

This article is categorized under:

• Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Harnessing an individual's immune cells to mediate antitumor and antiviral responses is a life-saving option for some patients with otherwise intractable forms of cancer and infectious disease. In particular, T-cell-based engineered immune cells are a powerful new class of therapeutics with remarkable efficacy. Clinical experience has helped to define some of the major challenges for reliable, safe, and effective deployment of T-cells against a broad range of diseases. While poised to revolutionize immunotherapy, scalable manufacturing, safety, specificity, and the development of resistance are potential roadblocks in their widespread usage. The development of molecular engineering tools to allow for the direct or indirect engineering of T-cells to enable one to troubleshoot delivery issues, amplify immunomodulatory effects, integrate the synergistic effects of different molecules, and home to the target cells in vivo. In this review, we will analyze thus-far developed cell- and material-based tools for enhancing T-cell therapies, including methods to improve safety and specificity, enhancing efficacy, and overcoming limitations in scalable manufacturing. We summarize the potential of T-cells as immune modulating therapies and the potential future directions for enabling their adoption for a broad range of diseases.

This article is categorized under:

• Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
• Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
• Nanotechnology Approaches to Biology > Cells at the Nanoscale

Immunotherapy has made great progress by modulating the body's own immune system to fight against cancer cells. However, the low response rates of related drugs limit the development of immunotherapy strategies. Fortunately, the advantages of nanotechnology can just make up for this shortcoming. Nanocarriers of diverse systems are utilized to co-deliver antigens and adjuvants, combined with drugs for immunomodulatory, such as chemotherapy, radiotherapy, and photodynamic. Here we review recent studies on immunotherapy with biomimetic, organic, and inorganic nanomaterials. They are going to potentially overcome the drawbacks in cancer immunotherapy with delivering immunomodulatory drugs, delivering cancer vaccine, and monitoring the immune systems.

This article is characterized under:

• Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease