Do Not Forget the Granulocytic Compartment's Role in T cell-Mediated Antitumor Immunity.

Antitumor immune responses are predominantly mediated by CD8+ cytotoxic T cells (CTLs). But immune-modulatory factors in the tumor microenvironment determine the effectiveness of these responses. In this issue, Wei and colleagues report a new role for CTL-derived IL3 in stimulating basophilic granulocytes to produce IL4, which, in turn, activates, reprograms, and stabilizes CTLs. These findings stress the importance of the crosstalk between the innate and adaptive immune systems to elicit efficient antitumor immunity. See related article by Wei et al., p. 822 (3).

Broadening anticancer spectrum by preprocessing and treatment of T- lymphocytes expressed FcγRI and monoclonal antibodies for refractory cancers.

Background: Chimeric antigen receptor T (CAR-T) cell therapies have achieved remarkable success in the treatment of hematological tumors. However, given the distinct features of solid tumors, particularly heterogeneity, metabolic aggressiveness, and fewer immune cells in tumor microenvironment (TME), the practical utility of CAR-T cells for solid tumors remains as a challenging issue. Meanwhile, although anti-PD-1 monoclonal antibody (mAb) has shown clinical efficacy, most mAbs also show limited clinical benefits for solid tumors due mainly to the issues associated with the lack of immune cells in TME. Thus, the infiltration of targeted immunological active cells into TME could generate synergistic efficacy for mAbs. Methods: We present a combinational strategy for solid tumor treatment, which combines armored-T cells to express Fc-gamma receptor I (FcγRI) fragment on the surfaces for targeting various tumors with therapeutically useful mAbs. Choosing CD20 and HER-2 as the targets, we characterized the in vitro and in vivo efficacy and latent mechanism of the combination drug by using flow cytometry, ELISA and other methods. Results: The combination and preprocessing of armored T-cells with corresponding antibody of Rituximab and Pertuzumab exerted profound anti-tumor effects, which is demonstrated to be mediated by synergistically produced antibody-dependent cellular cytotoxicity (ADCC) effects. Meanwhile, mAb was able to carry armored-T cell by preprocessing for the infiltration to TME in cell derived xenograft (CDX) model. Conclusions: This combination strategy showed a significant increase of safety profiles from the reduction of antibody doses. More importantly, the present strategy could be a versatile tool for a broad spectrum of cancer treatment, with a simple pairing of engineered T cells and a conventional antibody.

Molecular mimicry of SARS-COV-2 antigens as a possible natural anti-cancer preventive immunization.

Background: In the present study we investigated whether peptides derived from the entire SARS-CoV-2 proteome share homology to TAAs (tumor-associated antigens) and cross-reactive CD8+ T cell can be elicited by the BNT162b2 preventive vaccine or the SARS-CoV-2 natural infection. Methods and results: Viral epitopes with high affinity (<100nM) to the HLA-A*02:01 allele were predicted. Shared and variant-specific epitopes were identified. Significant homologies in amino acidic sequence have been found between SARS-CoV-2 peptides and multiple TAAs, mainly associated with breast, liver, melanoma and colon cancers. The molecular mimicry of the viral epitopes and the TAAs was found in all viral proteins, mostly the Orf 1ab and the Spike, which is included in the BNT162b2 vaccine. Predicted structural similarities confirmed the sequence homology and comparable patterns of contact with both HLA and TCR α and ß chains were observed. CD8+ T cell clones cross-reactive with the paired peptides have been found by MHC class l-dextramer staining. Conclusions: Our results show for the first time that several SARS-COV-2 antigens are highly homologous to TAAs and cross-reactive T cells are identified in infected and BNT162b2 preventive vaccinated individuals. The implication would be that the SARS-Cov-2 pandemic could represent a natural preventive immunization for breast, liver, melanoma and colon cancers. In the coming years, real-world evidences will provide the final proof for such immunological experimental evidence. Moreover, such SARS-CoV-2 epitopes can be used to develop "multi-cancer" off-the-shelf preventive/therapeutic vaccine formulations, with higher antigenicity and immunogenicity than over-expressed tumor self-antigens, for the potential valuable benefit of thousands of cancer patients around the World.

Unlocking the potential of pyroptosis in tumor immunotherapy: a new horizon in cancer treatment.

Background: The interaction between pyroptosis-a form of programmed cell death-and tumor immunity represents a burgeoning field of interest. Pyroptosis exhibits a dual role in cancer: it can both promote tumor development and counteract it by activating immune responses that inhibit tumor evasion and encourage cell death. Current tumor immunotherapy strategies, notably CAR-T cell therapy and immune checkpoint inhibitors (ICIs), alongside the potential of certain traditional Chinese medicinal compounds, highlight the intricate relationship between pyroptosis and cancer immunity. As research delves deeper into pyroptosis mechanisms within tumor therapy, its application in enhancing tumor immune responses emerges as a novel research avenue. Purpose: This review aims to elucidate the mechanisms underlying pyroptosis, its impact on tumor biology, and the advancements in tumor immunotherapy research. Methods: A comprehensive literature review was conducted across PubMed, Embase, CNKI, and Wanfang Database from the inception of the study until August 22, 2023. The search employed keywords such as "pyroptosis", "cancer", "tumor", "mechanism", "immunity", "gasdermin", "ICB", "CAR-T", "PD-1", "PD-L1", "herbal medicine", "botanical medicine", "Chinese medicine", "traditional Chinese medicine", "immunotherapy", linked by AND/OR, to capture the latest findings in pyroptosis and tumor immunotherapy. Results: Pyroptosis is governed by a complex mechanism, with the Gasdermin family playing a pivotal role. While promising for tumor immunotherapy application, research into pyroptosis's effect on tumor immunity is still evolving. Notably, certain traditional Chinese medicine ingredients have been identified as potential pyroptosis inducers, meriting further exploration. Conclusion: This review consolidates current knowledge on pyroptosis's role in tumor immunotherapy. It reveals pyroptosis as a beneficial factor in the immunotherapeutic landscape, suggesting that leveraging pyroptosis for developing novel cancer treatment strategies, including those involving traditional Chinese medicine, represents a forward-looking approach in oncology.

SOCS1 is a critical checkpoint in immune homeostasis, inflammation and tumor immunity.

The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental SOCS1 variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.

Next-Generation Vaccine Development with Nanomaterials: Recent Advances, Possibilities, and Challenges.

Nanomaterials are becoming important tools for vaccine development owing to their tunable and adaptable nature. Unique properties of nanomaterials afford opportunities to modulate trafficking through various tissues, complement or augment adjuvant activities, and specify antigen valency and display. This versatility has enabled recent work designing nanomaterial vaccines for a broad range of diseases, including cancer, inflammatory diseases, and various infectious diseases. Recent successes of nanoparticle vaccines during the coronavirus disease 2019 (COVID-19) pandemic have fueled enthusiasm further. In this review, the most recent developments in nanovaccines for infectious disease, cancer, inflammatory diseases, allergic diseases, and nanoadjuvants are summarized. Additionally, challenges and opportunities for clinical translation of this unique class of materials are discussed.

Engineering strategies to safely drive CAR T-cells into the future.

Chimeric antigen receptor (CAR) T-cell therapy has proven a breakthrough in cancer treatment in the last decade, giving unprecedented results against hematological malignancies. All approved CAR T-cell products, as well as many being assessed in clinical trials, are generated using viral vectors to deploy the exogenous genetic material into T-cells. Viral vectors have a long-standing clinical history in gene delivery, and thus underwent iterations of optimization to improve their efficiency and safety. Nonetheless, their capacity to integrate semi-randomly into the host genome makes them potentially oncogenic via insertional mutagenesis and dysregulation of key cellular genes. Secondary cancers following CAR T-cell administration appear to be a rare adverse event. However several cases documented in the last few years put the spotlight on this issue, which might have been underestimated so far, given the relatively recent deployment of CAR T-cell therapies. Furthermore, the initial successes obtained in hematological malignancies have not yet been replicated in solid tumors. It is now clear that further enhancements are needed to allow CAR T-cells to increase long-term persistence, overcome exhaustion and cope with the immunosuppressive tumor microenvironment. To this aim, a variety of genomic engineering strategies are under evaluation, most relying on CRISPR/Cas9 or other gene editing technologies. These approaches are liable to introduce unintended, irreversible genomic alterations in the product cells. In the first part of this review, we will discuss the viral and non-viral approaches used for the generation of CAR T-cells, whereas in the second part we will focus on gene editing and non-gene editing T-cell engineering, with particular regard to advantages, limitations, and safety. Finally, we will critically analyze the different gene deployment and genomic engineering combinations, delineating strategies with a superior safety profile for the production of next-generation CAR T-cell.

Universal CAR 2.0 to overcome current limitations in CAR therapy.

Chimeric antigen receptor (CAR) T cell therapy has effectively complemented the treatment of advanced relapsed and refractory hematological cancers. The remarkable achievements of CD19- and BCMA-CAR T therapies have raised high expectations within the fields of hematology and oncology. These groundbreaking successes are propelling a collective aspiration to extend the reach of CAR therapies beyond B-lineage malignancies. Advanced CAR technologies have created a momentum to surmount the limitations of conventional CAR concepts. Most importantly, innovations that enable combinatorial targeting to address target antigen heterogeneity, using versatile adapter CAR concepts in conjunction with recent transformative next-generation CAR design, offer the promise to overcome both the bottleneck associated with CAR manufacturing and patient-individualized treatment regimens. In this comprehensive review, we delineate the fundamental prerequisites, navigate through pivotal challenges, and elucidate strategic approaches, all aimed at paving the way for the future establishment of multitargeted immunotherapies using universal CAR technologies.

Modulatory effects of cancer stem cell-derived extracellular vesicles on the tumor immune microenvironment.

Cancer stem cells (CSCs), accounting for only a minor cell proportion (< 1%) within tumors, have profound implications in tumor initiation, metastasis, recurrence, and treatment resistance due to their inherent ability of self-renewal, multi-lineage differentiation, and tumor-initiating potential. In recent years, accumulating studies indicate that CSCs and tumor immune microenvironment act reciprocally in driving tumor progression and diminishing the efficacy of cancer therapies. Extracellular vesicles (EVs), pivotal mediators of intercellular communications, build indispensable biological connections between CSCs and immune cells. By transferring bioactive molecules, including proteins, nucleic acids, and lipids, EVs can exert mutual influence on both CSCs and immune cells. This interaction plays a significant role in reshaping the tumor immune microenvironment, creating conditions favorable for the sustenance and propagation of CSCs. Deciphering the intricate interplay between CSCs and immune cells would provide valuable insights into the mechanisms of CSCs being more susceptible to immune escape. This review will highlight the EV-mediated communications between CSCs and each immune cell lineage in the tumor microenvironment and explore potential therapeutic opportunities.

Advances in Bacterial Lysate Immunotherapy for Infectious Diseases and Cancer.

Antigenic cell fragments, pathogen-associated molecular patterns, and other immunostimulants in bacterial lysates or extracts may induce local and systemic immune responses in specific and nonspecific paradigms. Based on current knowledge, this review aimed to determine whether bacterial lysate has comparable functions in infectious diseases and cancer treatment. In infectious diseases, including respiratory and urinary tract infections, immune system activation by bacterial lysate can identify and combat pathogens. Commercially available bacterial lysates, including OM-85, Ismigen, Lantigen B, and LW 50020, were effective in children and adults in treating respiratory tract infections, chronic obstructive pulmonary disease, rhinitis, and rhinosinusitis with varying degrees of success. Moreover, OM-89, Uromune, Urovac, Urivac, and ExPEC4V showed therapeutic benefits in controlling urinary tract infections in adults, especially women. Bacterial lysate-based therapeutics are safe, well-tolerated, and have few side effects, making them a good alternative for infectious disease management. Furthermore, a nonspecific immunomodulation by bacterial lysates may stimulate innate immunity, benefiting cancer treatment. "Coley's vaccine" has been used to treat sarcomas, carcinomas, lymphomas, melanomas, and myelomas with varying outcomes. Later, several similar bacterial lysate-based therapeutics have been developed to treat cancers, including bladder cancer, non-small cell lung cancer, and myeloma; among them, BCG for in situ bladder cancer is well-known. Proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, may activate bacterial antigen-specific adaptive responses that could restore tumor antigen recognition and response by tumor-specific type 1 helper cells and cytotoxic T cells; therefore, bacterial lysates are worth investigating as a vaccination adjuvants or add-on therapies for several cancers.

Immune-related adverse events of antibody-based biological medicines in cancer therapy.

Recombinant antibodies (Abs) are an integral modality for the treatment of multiple tumour malignancies. Since the Food and Drug Administration (FDA) approval of rituximab as the first monoclonal antibody (mAb) for cancer treatment, several mAbs and antibody (Ab)-based therapies have been approved for the treatment of solid tumour malignancies and other cancers. These Abs function by either blocking oncogenic pathways or angiogenesis, modulating immune response, or by delivering a conjugated drug. The use of Ab-based therapy in cancer patients who could benefit from the treatment, however, is still limited by associated toxicity profiles which may stem from biological features and processes related to target binding, alongside biochemical and/or biophysical characteristics of the therapeutic Ab. A significant immune-related adverse event (irAE) associated with Ab-based therapies is cytokine release syndrome (CRS), characterized by the development of fever, rash and even marked, life-threatening hypotension, and acute inflammation with secondary to systemic uncontrolled increase in a range of pro-inflammatory cytokines. Here, we review irAEs associated with specific classes of approved, Ab-based novel cancer immunotherapeutics, namely immune checkpoint (IC)-targeting Abs, bispecific Abs (BsAbs) and Ab-drug-conjugates (ADCs), highlighting the significance of harmonization in preclinical assay development for safety assessment of Ab-based biotherapeutics as an approach to support and refine clinical translation.

The biological function of Serpinb9 and Serpinb9-based therapy.

Recent breakthroughs in discovering novel immune signaling pathways have revolutionized different disease treatments. SERPINB9 (Sb9), also known as Proteinase Inhibitor 9 (PI-9), is a well-known endogenous inhibitor of Granzyme B (GzmB). GzmB is a potent cytotoxic molecule secreted by cytotoxic T lymphocytes and natural killer cells, which plays a crucial role in inducing apoptosis in target cells during immune responses. Sb9 acts as a protective mechanism against the potentially harmful effects of GzmB within the cells of the immune system itself. On the other hand, overexpression of Sb9 is an important mechanism of immune evasion in diseases like cancers and viral infections. The intricate functions of Sb9 in different cell types represent a fine-tuned regulatory mechanism for preventing immunopathology, protection against autoimmune diseases, and the regulation of cell death, all of which are essential for maintaining health and responding effectively to disease challenges. Dysregulation of the Sb9 will disrupt human normal physiological condition, potentially leading to a range of diseases, including cancers, inflammatory conditions, viral infections or other pathological disorders. Deepening our understanding of the role of Sb9 will aid in the discovery of innovative and effective treatments for various medical conditions. Therefore, the objective of this review is to consolidate current knowledge regarding the biological role of Sb9. It aims to offer insights into its discovery, structure, functions, distribution, its association with various diseases, and the potential of nanoparticle-based therapies targeting Sb9.

Context-dependent T-BOX transcription factor family: from biology to targeted therapy.

T-BOX factors belong to an evolutionarily conserved family of transcription factors. T-BOX factors not only play key roles in growth and development but are also involved in immunity, cancer initiation, and progression. Moreover, the same T-BOX molecule exhibits different or even opposite effects in various developmental processes and tumor microenvironments. Understanding the multiple roles of context-dependent T-BOX factors in malignancies is vital for uncovering the potential of T-BOX-targeted cancer therapy. We summarize the physiological roles of T-BOX factors in different developmental processes and their pathological roles observed when their expression is dysregulated. We also discuss their regulatory roles in tumor immune microenvironment (TIME) and the newly arising questions that remain unresolved. This review will help in systematically and comprehensively understanding the vital role of the T-BOX transcription factor family in tumor physiology, pathology, and immunity. The intention is to provide valuable information to support the development of T-BOX-targeted therapy.

Mangiferin: A natural bioactive immunomodulating glucosylxanthone with potential against cancer and rheumatoid arthritis.

Mangiferin is a naturally occurring glucosylxanthone that has shown promising immunomodulatory effects. It is generally isolated from the leaves, peels, bark, and kernels of Mangifera indica Linn. Mangiferin is like a miraculous natural bioactive molecule that has an immunomodulatory function that makes it a potential therapeutic candidate for the treatment of rheumatoid arthritis (RA) and cancer. The anticancer activity of mangiferin acts by blocking NF-κB, as well as regulating the ß-catenin, EMT, MMP9, MMP2, LDH, ROS, and NO, and also by the activation of macrophages. It has no cytotoxic effect on grown chondrocytes and lowers matrix metalloproteinase levels. Additionally, it has a potent proapoptotic impact on synoviocytes. The precise molecular mechanism of action of mangiferin on RA and malignancies is still unknown. This comprehensive review elaborates on the immunomodulatory effect of mangiferin and its anticancer and anti-RA activity. This also explained the total synthesis of mangiferin and its in vitro and in vivo screening models.

Non B Cell-Derived Immunoglobulin, A Brighter Horizon for the Future.

The canonical theory of immunology stating that "Immunoglobulin (Ig) is produced by B lymphocytes and exerts antibody activity" has been established since the 1970s. However, the discovery of non B cell-derived Igs (non B-Igs), which can exert multiple biological activities in addition to their antibody activities, necessitates a reevaluation of the classic concept of Ig. This has been documented with a number of characteristics related to their structure, modification, genetic regulation as well as the functions associated with clinical conditions, particularly multiple cancers. The discovery of non B-Ig provides us with a new perspective to better understand not only basic immunology, but also various Ig-related clinical manifestations including autoimmune diseases, chronic inflammation, and anaphylaxis. Notably, non B-Ig can directly promote the occurrence of malignant tumours.

The Structure Characteristics and Function of Non B Cell-Derived Immunoglobulin.

According to classical immunology theory, immunoglobulin (Ig) is exclusively produced by differentiated B lymphocytes, which exhibit a typical tetrapeptide chain structure and are predominantly present on the surface of B cells and in bodily fluids. B-Ig is one of the critical effector molecules for humoral immune responses specifically recognising antigens and eliminating them. However, mounting evidence has demonstrated that Ig is widely expressed in non B lineage cells, especially malignant ones (referred to as non B-Ig). Interestingly, non B-Ig mainly resides in the cytoplasm and secretion, but to some extent on the cell surface. Furthermore non B-Ig not only displays a tetrapeptide chain structure but also shows free heavy chains and free light chains (FLCs). Additionally, Ig derived from non B cancer cell typically displays unique glycosylation modifications. Functionally, non B-Ig demonstrated diversity and versatility, showing antibody activity and cellular biological activity, such as promoting cell proliferation and survival, and it is implicated in cancer progression and some immune-related diseases, such as renal diseases.

Comparison of Non B-Ig and B-Ig.

Immunoglobulin (Ig) has been widely acknowledged to be produced solely by B-lineage cells. However, growing evidence has demonstrated the expression of Ig in an array of cancer cells, as well as normal cells including epithelial cells, epidermal cells, mesangial cells, monocytes, and neutrophils. Ig has even been found to be expressed in non-B cells at immune-privileged sites such as neurons and spermatogenic cells. Despite these non-B cell-derived Igs (non-B-Igs) sharing the same symmetric structures with conventional Igs (B-Igs), further studies have revealed unique characteristics of non-B-Ig, such as restricted variable region and aberrant glycosylation. Moreover, non-B-Ig exhibits properties of promoting malignant behaviours of cancer cells, therefore it could be utilised in the clinic as a potential therapeutic biomarker or target. The elucidation of the generation and regulation of non-B-Ig will certainly broaden our understanding of immunology.

Differences in the risk of immune-related pneumonitis between PD-1 and PD-L1 inhibitors: a meta-analysis according to the new mirror-principle and PRISMA guidelines.

PURPOSE: To compare the risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors, the meta-analysis was designed. METHOD: The difference in risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors was assessed by two different meta-analysis methods, the Mirror-pairing and the PRISMA guidelines. RESULTS: A total of eighty-eight reports were used for meta-analysis, while thirty-two studies were used for the Mirror-pairing. Both PD-1 and PD-L1 inhibitors (used alone or combined with chemotherapy) increased the risk of developing immune-related pneumonitis (P < 0.00001; P < 0.00001). Based on indirect analyses results (subgroup analyses), the risk of PD-L1-induced pneumonitis was weaker than that of PD-1 inhibitors when the control group was chemotherapy (OR = 3.33 vs. 5.43) or placebo (OR = 2.53 vs. 3.19), while no obvious significant differences were found (P = 0.17; P = 0.53). For the Mirror-pairing-based meta-analysis, the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors (OR = 1.46, 95%CI [1.08, 1.98], I2 = 0%, Z = 2.47 (P = 0.01)). However, this difference was not significant, when they were combined with chemotherapy (OR = 1.05, 95%CI [0.68, 1.60], I2 = 38%, Z = 0.21 (P = 0.84)). CONCLUSION: Both PD-1 and PD-L1 inhibitors increased the risk of immune-related pneumonitis, while the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors.