The successful outcomes of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic cancers have increased the previously unprecedented excitement to use this innovative approach in treating various forms of human cancers. Although researchers have put a lot of work into maximizing the effectiveness of these cells in the context of solid tumors, few studies have discussed challenges and potential strategies to overcome them. Restricted trafficking and infiltration into the tumor site, hypoxic and immunosuppressive tumor microenvironment (TME), antigen escape and heterogeneity, CAR T-cell exhaustion, and severe life-threatening toxicities are a few of the major obstacles facing CAR T-cells. CAR designs will need to go beyond the traditional architectures in order to get over these limitations and broaden their applicability to a larger range of malignancies. To enhance the safety, effectiveness, and applicability of this treatment modality, researchers are addressing the present challenges with a wide variety of engineering strategies as well as integrating several therapeutic tactics. In this study, we reviewed the antigens that CAR T-cells have been clinically trained to recognize, as well as counterstrategies to overcome the limitations of CAR T-cell therapy, such as recent advances in CAR T-cell engineering and the use of several therapies in combination to optimize their clinical efficacy in solid tumors.

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1113882/pdf

The current landscape of CAR T-cell therapy for solid tumors: Mechanisms, research progress, challenges, and counterstrategies

The incidence of cancer is increasing dramatically, affecting all ages of the population and reaching an ever higher worldwide mortality rate. The lack of therapies’ efficacy is due to several factors such as a delay in diagnosis, tumor regrowth after surgical resection and the occurrence of multidrug resistance (MDR). Tumor-associated immune cells and the tumor microenvironment (TME) deeply affect the tumor’s progression, leading to several physicochemical changes compared to physiological conditions. In this scenario, macrophages play a crucial role, participating both in tumor suppression or progression based on the polarization of onco-suppressive M1 or pro-oncogenic M2 phenotypes. Moreover, much evidence supports the pivotal role of macrophage-derived extracellular vesicles (EVs) as mediators in TME, because of their ability to shuttle the cell–cell and organ–cell communications, by delivering nucleic acids and proteins. EVs are lipid-based nanosystems with a broad size range distribution, which reflect a similar composition of native parent cells, thus providing a natural selectivity towards target sites. In this review, we discuss the impact of macrophage-derived EVs in the cancer’s fate as well as their potential implications for the development of personalized anticancer nanomedicine.

/pdf/macrophage-derived-extracellular-vesicles-a-promising-tool-14lnzs7c.pdf

Macrophage-Derived Extracellular Vesicles: A Promising Tool for Personalized Cancer Therapy

Sex-specific differences may contribute to Alzheimer’s disease (AD) development. AD is more prevalent in women worldwide, and female sex has been suggested as a disease risk factor. Nevertheless, the molecular mechanisms underlying sex-biased differences in AD remain poorly characterized. To this end, we analyzed the transcriptional changes in the entorhinal cortex of symptomatic and asymptomatic AD patients stratified by sex. Co-expression network analysis implemented by SWItchMiner software identified sex-specific signatures of switch genes responsible for drastic transcriptional changes in the brain of AD and asymptomatic AD individuals. Pathway analysis of the switch genes revealed that morphine addiction, retrograde endocannabinoid signaling, and autophagy are associated with both females with AD (F-AD) and males with (M-AD). In contrast, nicotine addiction, cell adhesion molecules, oxytocin signaling, adipocytokine signaling, prolactin signaling, and alcoholism are uniquely associated with M-AD. Similarly, some of the unique pathways associated with F-AD switch genes are viral myocarditis, Hippo signaling pathway, endometrial cancer, insulin signaling, and PI3K-AKT signaling. Together these results reveal that there are many sex-specific pathways that may lead to AD. Approximately 20–30% of the elderly have an accumulation of amyloid beta in the brain, but show no cognitive deficit. Asymptomatic females (F-asymAD) and males (M-asymAD) both shared dysregulation of endocytosis. In contrast, pathways uniquely associated with F-asymAD switch genes are insulin secretion, progesterone-mediated oocyte maturation, axon guidance, renal cell carcinoma, and ErbB signaling pathway. Similarly, pathways uniquely associated with M-asymAD switch genes are fluid shear stress and atherosclerosis, FcγR mediated phagocytosis, and proteoglycans in cancer. These results reveal for the first time unique pathways associated with either disease progression or cognitive resilience in asymptomatic individuals. Additionally, we identified numerous sex-specific transcription factors and potential neurotoxic chemicals that may be involved in the pathogenesis of AD. Together these results reveal likely molecular drivers of sex differences in the brain of AD patients. Future molecular studies dissecting the functional role of these switch genes in driving sex differences in AD are warranted.

/pdf/sex-specific-transcriptional-rewiring-in-the-brain-of-2mcic8ec.pdf

Sex-specific transcriptional rewiring in the brain of Alzheimer’s disease patients

In many hematologic malignancies, the adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated notable success; nevertheless, further improvements are necessary to optimize treatment efficacy. Current CAR-T therapies are particularly discouraging for solid tumor treatment. The immunosuppressive microenvironment of tumors affects CAR-T cells, limiting the treatment's effectiveness and safety. Therefore, enhancing CAR-T cell infiltration capacity and resolving the immunosuppressive responses within the tumor microenvironment could boost the anti-tumor effect. Specific strategies include structurally altering CAR-T cells combined with targeted therapy, radiotherapy, or chemotherapy. Overall, monitoring the tumor microenvironment and the status of CAR-T cells is beneficial in further investigating the viability of such strategies and advancing CAR-T cell therapy. 

Reshaping the tumor immune microenvironment to improve CAR-T cell-based cancer immunotherapy

Background Melanoma is a skin tumor with a high mortality rate, and early diagnosis and effective treatment are the key to reduce its mortality rate. Therefore, more and more attention has been paid for biomarker identification for early diagnosis, prognosis prediction and prognosis evaluation of melanoma. However, there is still a lack of a report that comprehensively and objectively evaluates the research status of melanoma biomarkers. Therefore, this study aims to intuitively analyze the research status and trend of melanoma biomarkers through the methods of bibliometrics and knowledge graph. Objective This study uses bibliometrics to analyze research in biomarkers in melanoma, summarize the field’s history and current status of research, and predict future research directions. Method Articles and Reviews related to melanoma biomarkers were retrieved by using Web of Science core collection subject search. Bibliometric analysis was performed in Excel 365, CiteSpace, VOSviewer and Bibliometrix (R-Tool of R-Studio). Result A total of 5584 documents from 2004 to 2022 were included in the bibliometric analysis. The results show that the number of publications and the frequency of citations in this field are increasing year by year, and the frequency of citations has increased rapidly after 2018. The United States is the most productive and influential country in this field, with the largest number of publications and institutions with high citation frequency. Caroline Robert, F. Stephen Hodi, Suzanne L. Topalian and others are authoritative authors in this field, and The New England Journal of Medicine, Journal of Clinical Oncology and Clinical Cancer Research are the most authoritative journals in this field. Biomarkers related to the diagnosis, treatment and prognosis of melanoma are hot topics and cutting-edge hotspots in this field. Conclusion For the first time, this study used the bibliometric method to visualize the research in the field of melanoma biomarkers, revealing the trends and frontiers of melanoma biomarkers research, which provides a useful reference for scholars to find key research issues and partners.

/pdf/mapping-knowledge-landscapes-and-emerging-trends-of-the-192tnddr.pdf

Mapping knowledge landscapes and emerging trends of the biomarkers in melanoma: a bibliometric analysis from 2004 to 2022

Abstract Atherosclerosis, which is the fundamental basis for cardiovascular diseases in the global world, is driven by multiple roles of the immune system in the circulation and vascular plaque. Recent studies demonstrated that T-cell infiltrates into aorta plaque and plays an important role in recruiting macrophages to the vascular wall. Here, using single-cell sequencing, we found T cells in patients’ plaques and differentially expressed genes (DEGs) of T cells in atherosclerosis mice. T cells and macrophages were continuously activated in atherosclerotic plaque in patients. Besides, other immune cells also take part in atherogenesis, such as natural killer (NK) cells, granulocytes. Interferon (IFN)/NFκB signaling, the AKT signaling pathway was highly activated in mouse (in vivo) and cell line (in vitro). TCF7 and XCL1 were regulated by AKT and NFκB, respectively through protein–protein network analysis. Therefore, we attempt to clarify and discover potential genes and new mechanisms associated with atherosclerosis for drug development.

https://portlandpress.com/bioscirep/article-pdf/doi/10.1042/BSR20212064/934715/bsr-2021-2064.pdf

TCF7 is highly expressed in immune cells on the atherosclerotic plaques, and regulating inflammatory signaling via NFκB/AKT/STAT1 signaling

Stat5−/− CD4+ T cells elicit anti-melanoma effect by CD4+ T cell remolding and Notch1 activation

Currently, the antitumor efficacy of chimeric antigen receptor T cells in solid tumors is modest. Both chemokines and their receptors play a key role in the proliferation of cancer cells, tumor angiogenesis, organ-selective metastasis and migration of immune cells to solid tumors. Unfortunately, frequent chemokine/chemokine receptor 'mismatch' between effector cells and the tumor microenvironment results in inefficient T-cell infiltration and antitumor efficacy. Thus, reversing the 'mismatch' of chemokines and chemokine receptors appears to be a promising method for promoting T-cell infiltration into the tumor and enhancing their antitumor efficacy. In this review, we discuss functions of the chemokine/chemokine receptor axis in cancer immunity and the current understanding, challenges and prospects for improving the effect of chimeric antigen receptor T cells by reversing the mismatch between chemokines and chemokine receptors.

Reversing chemokine/chemokine receptor mismatch to enhance the antitumor efficacy of CAR-T cells.

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TCF7 is highly expressed in immune cells on the atherosclerotic plaques, and regulating inflammatory signaling via NFκB/AKT/STAT1 signaling

Stat5−/− CD4+ T cells elicit anti-melanoma effect by CD4+ T cell remolding and Notch1 activation

Reversing chemokine/chemokine receptor mismatch to enhance the antitumor efficacy of CAR-T cells.