Simple Summary Breast cancer is the most prevalent malignancy in women. With the improvement of medical treatment, breast cancer has become one of the solid tumors with the best curative effect. However, triple-negative breast cancer is not sensitive to conventional treatment due to its high invasiveness, resulting in a poorer prognosis than other types. The antibodies of programmed death receptor 1 and its ligands represent a new option as immunotherapy for patients with triple negative breast cancer. However, some recent clinical data suggest that a large proportion of patients exhibit primary or acquired resistance to treatment with programmed death receptor antibodies. In this review, we discuss the mechanisms that lead to resistance and also summarize potential strategies to overcome the resistance, improving the therapeutic efficacy of programmed death receptor 1 and its ligand-based antibodies in triple negative breast cancer. Abstract Triple-negative breast cancer (TNBC) is characterized by a high rate of systemic metastasis, insensitivity to conventional treatment and susceptibility to drug resistance, resulting in a poor patient prognosis. The immune checkpoint inhibitors (ICIs) represented by antibodies of programmed death receptor 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have provided new therapeutic options for TNBC. However, the efficacy of PD-1/PD-L1 blockade monotherapy is suboptimal immune response, which may be caused by reduced antigen presentation, immunosuppressive tumor microenvironment, interplay with other immune checkpoints and aberrant activation of oncological signaling in tumor cells. Therefore, to improve the sensitivity of TNBC to ICIs, suitable patients are selected based on reliable predictive markers and treated with a combination of ICIs with other therapies such as chemotherapy, radiotherapy, targeted therapy, oncologic virus and neoantigen-based therapies. This review discusses the current mechanisms underlying the resistance of TNBC to PD-1/PD-L1 inhibitors, the potential biomarkers for predicting the efficacy of anti-PD-1/PD-L1 immunotherapy and recent advances in the combination therapies to increase response rates, the depth of remission and the durability of the benefit of TNBC to ICIs.

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Mechanisms and Strategies to Overcome PD-1/PD-L1 Blockade Resistance in Triple-Negative Breast Cancer

The mechanisms of antigen processing and presentation play a crucial role in the recognition and targeting of cancer cells by the immune system. Cancer cells can evade the immune system by downregulating or losing the expression of the proteins recognized by the immune cells as antigens, creating an immunosuppressive microenvironment, and altering their ability to process and present antigens. This review focuses on the mechanisms of cancer immune evasion with a specific emphasis on the role of antigen presentation machinery. The study of the immunopeptidome, or peptidomics, has provided insights into the mechanisms of cancer immune evasion and has potential applications in cancer diagnosis and treatment. Additionally, manipulating the epigenetic landscape of cancer cells plays a critical role in suppressing the immune response against cancer. Targeting these mechanisms through the use of HDACis, DNMTis, and combination therapies has the potential to improve the efficacy of cancer immunotherapy. However, further research is needed to fully understand the mechanisms of action and optimal use of these therapies in the clinical setting. 

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Cancer immune escape: the role of antigen presentation machinery

Lymph node metastasis, the leading cause of mortality in esophageal squamous carcinoma (ESCC) with a highly complex tumor microenvironment, remains underexplored. Here, the transcriptomes of 85 263 single cells are analyzed from four ESCC patients with lymph node metastases. Strikingly, it is observed that the metastatic microenvironment undergoes the emergence or expansion of interferon induced IFIT3+ T, B cells, and immunosuppressive cells such as APOC1+APOE+ macrophages and myofibroblasts with highly expression of immunoglobulin genes (IGKC) and extracellular matrix component and matrix metallopeptidase genes. A poor‐prognostic epithelial‐immune dual expression program regulating immune effector processes, whose activity is significantly enhanced in metastatic malignant epithelial cells and enriched in CD74+CXCR4+ and major histocompatibility complex (MHC) class II genes upregulated malignant epithelia cells is discovered. Comparing with primary tumor, differential intercellular communications of metastatic ESCC microenvironment are revealed and furtherly validated via multiplexed immunofluorescence and immunohistochemistry staining, which mainly rely on the crosstalk of APOC1+APOE+ macrophages with tumor and stromal cell. The data highlight potential molecular mechanisms that shape the lymph‐node metastatic microenvironment and may inform drug discovery and the development of new strategies to target these prometastatic nontumor components for inhibiting tumor growth and overcoming metastasis to improve clinical outcomes.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202204565

Single‐Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Esophageal Squamous Cell Carcinoma

mRNA vaccines encoding tumor antigens may be able to sensitize the immune system of the host against cancer cells, enhancing antigen presentation and immune response. Since the breakout of the COVID19 pandemic, interest in mRNA vaccines has been accelerating, as vaccination against the virus served as a measure to limit disease spread. Given that immunotherapy has been the cornerstone of melanoma treatment over the last several decades, further innate immunity enhancement by targeted mRNA vaccines could be the next pivotal achievement in melanoma treatment. Preclinical data coming from murine cancer models have already provided evidence of mRNA vaccines’ ability to induce host immune responses against cancer. Moreover, specific immune responses have been observed in melanoma patients receiving mRNA vaccines, while the recent KEYNOTE-942 trial may establish the incorporation of the mRNA-4157/V940 vaccine into the melanoma treatment algorithm, in combination with immune checkpoint inhibition. As the existing data are further tested and reviewed, investigators are already gaining enthusiasm about this novel, promising pathway in cancer therapy.

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Evolution and Progress of mRNA Vaccines in the Treatment of Melanoma: Future Prospects

Cancer-associated gene fusions, also known as oncofusions, have emerged as influential drivers of oncogenesis across a diverse range of cancer types. These genetic events occur via chromosomal translocations, deletions, and inversions, leading to the fusion of previously separate genes. Due to the drastic nature of these mutations, they often result in profound alterations of cellular behavior. The identification of oncofusions has revolutionized cancer research, with advancements in sequencing technologies facilitating the discovery of novel fusion events at an accelerated pace. Oncofusions exert their effects through the manipulation of critical cellular signaling pathways that regulate processes such as proliferation, differentiation, and survival. Extensive investigations have been conducted to understand the roles of oncofusions in solid tumors, leukemias, and lymphomas. Large-scale initiatives, including the Cancer Genome Atlas, have played a pivotal role in unraveling the landscape of oncofusions by characterizing a vast number of cancer samples across different tumor types. While validating the functional relevance of oncofusions remains a challenge, even non-driver mutations can hold significance in cancer treatment. Oncofusions have demonstrated potential value in the context of immunotherapy through the production of neoantigens. Their clinical importance has been observed in both treatment and diagnostic settings, with specific fusion events serving as therapeutic targets or diagnostic markers. However, despite the progress made, there is still considerable untapped potential within the field of oncofusions. Further research and validation efforts are necessary to understand their effects on a functional basis and to exploit the new targeted treatment avenues offered by oncofusions. Through further functional and clinical studies, oncofusions will enable the advancement of precision medicine and the drive towards more effective and specific treatments for cancer patients.

Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies

Abstract Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy and antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations, such as genomic mutation, dysregulated RNA splicing, disordered post-translational modification, and integrated viral open reading frames. Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance. The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies. Compared to tumor-associated antigens, the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies, and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses. The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies. This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens. We also explore their current status, inherent challenges, and clinical translation potential. 

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Neoantigens: promising targets for cancer therapy

Abstract Invasive cancer growth and metastasis account for the poor prognosis of high‐grade breast cancer. Recently, we reported that kinectin 1 (KTN1), a member of the kinesin‐binding protein family, promotes cell invasion of triple‐negative breast cancer and high‐grade breast cancer cells by augmenting the NF‐κB signaling pathway. However, the upstream mechanism regulating KTN1 is unknown. Therefore, this functional study was performed to decipher the regulatory cohort of KTN1 in high‐grade breast cancer. Bioinformatic analysis indicated that transcription factor Yin Yang 1 (YY1) was a potential transactivator of KTN1. High YY1 expression correlated positively with pathological progression and poor prognosis of high‐grade breast cancer. Additionally, YY1 promoted cell invasive growth both in vitro and in vivo, in a KTN1‐dependent manner. Mechanistically, YY1 could transactivate the KTN1 gene promoter. Alternatively, YY1 could directly interact with a co‐factor, DEAD‐box helicase 3 X‐linked (DDX3X), which significantly co‐activated YY1‐mediated transcriptional expression of KTN1. Moreover, DDX3X augmented YY1‐KTN1 signaling‐promoted invasive cell growth of breast cancer. Importantly, overexpression of YY1 enhanced tumor aggressive growth in a mouse breast cancer model. Our findings established a novel DDX3X‐assisted YY1‐KTN1 regulatory axis in breast cancer progression, which could lead to the development novel therapeutic targets for breast cancer.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/mco2.133

Yin Yang 1 promotes aggressive cell growth in high‐grade breast cancer by directly transactivating kinectin 1

Rationally designed and engineered bacteria represent an emerging unique approach for cancer treatment. Here, we engineer a short-lived bacterium, mp105, that is effective against diverse cancer types and safe for intravenous administration. We reveal that mp105 combats cancer by direct oncolysis, depletion of tumor-associated macrophages, and elicitation of CD4+ T cell immunity. We further engineer a glucose-sensing bacterium named m6001 that selectively colonizes solid tumors. When intratumorally injected, m6001 clears tumors more efficiently than mp105 due to its post-delivery replication in tumors and potent oncolytic capacity. Finally, we combine intravenous injection of mp105 and intratumoral injection of m6001, forming a double team against cancer. The double team enhances cancer therapy compared with single treatment for subjects carrying both intratumorally injectable and uninjectable tumors. The two anticancer bacteria and their combination are applicable to different scenarios, turning bacterial therapy for cancer into a feasible solution. 

http://www.cell.com/article/S266637912300157X/pdf

Engineer a double team of short-lived and glucose-sensing bacteria for cancer eradication

Abstract Purpose Esophageal squamous cell carcinoma (ESCC) remains one of the most common causes of cancer death due to the lack of effective therapeutic options. New targets and the targeted drugs are required to be identified and developed. Methods Highly expressed genes in ESCA were identified using the edgeR package from public datasets. Immunostaining assay verified the high expression level of EFNA1 in ESCC. CCK-8, colony formation and wound healing assays were performed to examine the role of EFNA1 and EPHA2 in ESCC progression. Cell cycle was analyzed by flow cytometry and autophagy activation was determined by autophagolysosome formation using transmission electron microscopy. The small molecule targeting to EFNA1 was identified by molecular docking and the anti-tumor effects were verified by in vitro and in vivo models with radiation treatment. Results EFNA1 was highly expressed in esophageal cancer and significantly associated with poor prognosis. Downregulation of EFNA1 remarkably inhibited cell proliferation and migration. Furthermore, decreased EFNA1 significantly suppressed the expression of cMYC along with its representative downstream genes involved in cell cycle, and activated autophagy. Similar effects on ESCC progression were obtained from knockdown of the corresponding receptor, EPHA2. The potential small molecule targeting to EFNA1, salvianolic acid A (SAA), could significantly suppress ESCC progression and increase the sensitivity to radiotherapy. Conclusion We revealed that EFNA1 facilitated the ESCC progression via the possible mechanism of activating cMYC-modulated cell proliferation and suppressing autophagy, and identified SAA as a potential drug targeting EFNA1, providing new options for the future treatments for ESCC patients. 

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Li Fu

Papers

Neoantigens: promising targets for cancer therapy

Single‐Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Esophageal Squamous Cell Carcinoma

Yin Yang 1 promotes aggressive cell growth in high‐grade breast cancer by directly transactivating kinectin 1

Engineer a double team of short-lived and glucose-sensing bacteria for cancer eradication

Targeting EFNA1 suppresses tumor progression via the cMYC-modulated cell cycle and autophagy in esophageal squamous cell carcinoma