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Cell Aug 2023The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide...
The T cells of the immune system can target tumors and clear solid cancers following tumor-infiltrating lymphocyte (TIL) therapy. We used combinatorial peptide libraries and a proteomic database to reveal the antigen specificities of persistent cancer-specific T cell receptors (TCRs) following successful TIL therapy for stage IV malignant melanoma. Remarkably, individual TCRs could target multiple different tumor types via the HLA A02:01-restricted epitopes EAAGIGILTV, LLLGIGILVL, and NLSALGIFST from Melan A, BST2, and IMP2, respectively. Atomic structures of a TCR bound to all three antigens revealed the importance of the shared x-x-x-A/G-I/L-G-I-x-x-x recognition motif. Multi-epitope targeting allows individual T cells to attack cancer in several ways simultaneously. Such "multipronged" T cells exhibited superior recognition of cancer cells compared with conventional T cell recognition of individual epitopes, making them attractive candidates for the development of future immunotherapies.
Topics: Antigens, Neoplasm; Epitopes; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Neoplasms; Proteomics; Receptors, Antigen, T-Cell
PubMed: 37490916
DOI: 10.1016/j.cell.2023.06.020 -
Molecular Cancer Jun 2023Cancer is the most prevalent cause of death globally, and radiotherapy is considered the standard of care for most solid tumors, including lung, breast, esophageal, and... (Review)
Review
BACKGROUND
Cancer is the most prevalent cause of death globally, and radiotherapy is considered the standard of care for most solid tumors, including lung, breast, esophageal, and colorectal cancers and glioblastoma. Resistance to radiation can lead to local treatment failure and even cancer recurrence.
MAIN BODY
In this review, we have extensively discussed several crucial aspects that cause resistance of cancer to radiation therapy, including radiation-induced DNA damage repair, cell cycle arrest, apoptosis escape, abundance of cancer stem cells, modification of cancer cells and their microenvironment, presence of exosomal and non-coding RNA, metabolic reprogramming, and ferroptosis. We aim to focus on the molecular mechanisms of cancer radiotherapy resistance in relation to these aspects and to discuss possible targets to improve treatment outcomes.
CONCLUSIONS
Studying the molecular mechanisms responsible for radiotherapy resistance and its interactions with the tumor environment will help improve cancer responses to radiotherapy. Our review provides a foundation to identify and overcome the obstacles to effective radiotherapy.
Topics: Humans; Neoplasm Recurrence, Local; Glioblastoma; Apoptosis; Treatment Outcome; Breast; Tumor Microenvironment
PubMed: 37322433
DOI: 10.1186/s12943-023-01801-2 -
Annual Review of Medicine Jan 2024Antibody-drug conjugates (ADCs) have become the cornerstone of effective therapeutics in solid and hematological malignancies by harnessing potent cytotoxic payloads... (Review)
Review
Antibody-drug conjugates (ADCs) have become the cornerstone of effective therapeutics in solid and hematological malignancies by harnessing potent cytotoxic payloads with targeted tumoricidal delivery. Since the monumental shift occurred with HER2-targeted ADCs, the discovery of the TROP2 antigen has revolutionized the landscape of ADC development. Moving beyond the traditional ADC design, multiple novel ADCs have successfully shaped and improved survival outcomes in patients with various tumor histologies. Here we review and contrast the clinical impact of the well-known TROP2 ADCs currently in clinical use. We also shed light on upcoming investigational TROP2 ADCs showing promise with novel ADC platforms.
Topics: Humans; Immunoconjugates; Neoplasms; Antineoplastic Agents; Hematologic Neoplasms
PubMed: 37758237
DOI: 10.1146/annurev-med-071322-065903 -
Biochimica Et Biophysica Acta. Reviews... Jul 2023The development of new antitumor drugs depends mainly upon targeting tumor cells precisely. Trophoblast surface antigen 2 (Trop-2) is a type I transmembrane glycoprotein... (Review)
Review
The development of new antitumor drugs depends mainly upon targeting tumor cells precisely. Trophoblast surface antigen 2 (Trop-2) is a type I transmembrane glycoprotein involved in Ca signaling in tumor cells. It is highly expressed in various tumor tissues than in normal tissues and represents a novel and promising molecular target for caner targeted therapy. Up to now, the mechanisms and functions associated with Trop-2 have been extensively studied in a variety of solid tumors. According to these findings, Trop-2 plays an important role in cell proliferation, apoptosis, cell adhesion, epithelial-mesenchymal transition, as well as tumorigenesis and tumor progression. In addition, Trop-2 related drugs are also being developed widely. There are a number of Trop-2 related ADC drugs that have demonstrated potent antitumor activity and are currently been studied, such as Sacituzumab Govitecan (SG) and Datopotamab Deruxtecan (Dato-Dxd). In this study, we reviewed the progress of Trop-2 research in solid tumors. We also sorted out the composition and rationale of Trop-2 related drugs and summarized the related clinical trials. Finally, we discussed the current status of Trop-2 research and expanded our perspectives on its future research directions. Importantly, we found that Trop-2 targeted ADCs have great potential for combination with other antitumor therapies. Trop-2 targeted ADCs can reprogramme tumor microenvironment through multiple signaling pathways, ultimately activating antitumor immunity.
Topics: Humans; Neoplasms; Antineoplastic Agents; Apoptosis; Tumor Microenvironment
PubMed: 37121444
DOI: 10.1016/j.bbcan.2023.188902 -
Cells Jun 2023Adoptive cell therapy using chimeric antigen receptor (CAR) technology is one of the most advanced engineering platforms for cancer immunotherapy. CAR-T cells have shown... (Review)
Review
Adoptive cell therapy using chimeric antigen receptor (CAR) technology is one of the most advanced engineering platforms for cancer immunotherapy. CAR-T cells have shown remarkable efficacy in the treatment of hematological malignancies. However, their limitations in solid tumors include an immunosuppressive tumor microenvironment (TME), insufficient tumor infiltration, toxicity, and the absence of tumor-specific antigens. Although recent advances in CAR-T cell design-such as the incorporation of co-stimulatory domains and the development of armored CAR-T cells-have shown promising results in treating solid tumors, there are still challenges that need to be addressed. To overcome these limitations, other immune cells, such as natural killer (NK) cells and macrophages (M), have been developed as attractive options for efficient cancer immunotherapy of solid tumors. CAR-NK cells exhibit substantial clinical improvements with "off-the-shelf" availability and low toxicity. CAR-M cells have promising therapeutic potential because macrophages can infiltrate the TME of solid tumors. Here, we review the recent advances and future perspectives associated with engineered immune cell-based cancer immunotherapies for solid tumors. We also summarize ongoing clinical trials investigating the safety and efficacy of engineered immune cells, such as CAR-T, CAR-NK, and CAR-M, for targeting solid tumors.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Neoplasms; Immunotherapy; T-Lymphocytes; Antigens, Neoplasm; Tumor Microenvironment
PubMed: 37371075
DOI: 10.3390/cells12121606 -
Cell Reports Aug 2023Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we...
Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors.
Topics: Animals; Mice; Cell Hypoxia; Cell Line, Tumor; Ferroptosis; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lactic Acid; Neoplasms; Tumor Microenvironment; Excitatory Amino Acid Transporter 3
PubMed: 37542723
DOI: 10.1016/j.celrep.2023.112945 -
Molecular Cancer Aug 2023Recent advances in neoantigen research have accelerated the development of tumor immunotherapies, including adoptive cell therapies (ACTs), cancer vaccines and... (Review)
Review
Recent advances in neoantigen research have accelerated the development of tumor immunotherapies, including adoptive cell therapies (ACTs), cancer vaccines and antibody-based therapies, particularly for solid tumors. With the development of next-generation sequencing and bioinformatics technology, the rapid identification and prediction of tumor-specific antigens (TSAs) has become possible. Compared with tumor-associated antigens (TAAs), highly immunogenic TSAs provide new targets for personalized tumor immunotherapy and can be used as prospective indicators for predicting tumor patient survival, prognosis, and immune checkpoint blockade response. Here, the identification and characterization of neoantigens and the clinical application of neoantigen-based TCR-T immunotherapy strategies are summarized, and the current status, inherent challenges, and clinical translational potential of these strategies are discussed.
Topics: Humans; Prospective Studies; Neoplasms; Cancer Vaccines; T-Lymphocytes; Receptors, Antigen, T-Cell
PubMed: 37649123
DOI: 10.1186/s12943-023-01844-5 -
Journal of Translational Medicine Jul 2023Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages... (Review)
Review
Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.
Topics: Humans; Receptors, Chimeric Antigen; Artificial Intelligence; Neoplasms; Immunotherapy, Adoptive; Antigens, Neoplasm; Multiple Myeloma; Hematologic Neoplasms; Tumor Microenvironment; Cell- and Tissue-Based Therapy
PubMed: 37420216
DOI: 10.1186/s12967-023-04292-3 -
Ugeskrift For Laeger Apr 2024Lung cancer is the leading cause of cancer-related death in Denmark and the world. The increase in CT examinations has led to an increase in detection of pulmonary... (Review)
Review
Lung cancer is the leading cause of cancer-related death in Denmark and the world. The increase in CT examinations has led to an increase in detection of pulmonary nodules divided into solid and subsolid (including ground glass and part solid). Risk factors for malignancy include age, smoking, female gender, and specific ethnicities. Nodule traits like size, spiculation, upper-lobe location, and emphysema correlate with higher malignancy risk. Managing these potentially malignant nodules relies on evidence-based guidelines and risk stratification. These risk stratification models can standardize the approach for the management of incidental pulmonary findings, as argued in this review.
Topics: Humans; Female; Tomography, X-Ray Computed; Solitary Pulmonary Nodule; Multiple Pulmonary Nodules; Lung Neoplasms; Lung
PubMed: 38606710
DOI: 10.61409/V09230595 -
Cell Mar 2024The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of... (Review)
Review
The integration of cancer biomarkers into oncology has revolutionized cancer treatment, yielding remarkable advancements in cancer therapeutics and the prognosis of cancer patients. The development of personalized medicine represents a turning point and a new paradigm in cancer management, as biomarkers enable oncologists to tailor treatments based on the unique molecular profile of each patient's tumor. In this review, we discuss the scientific milestones of cancer biomarkers and explore future possibilities to improve the management of patients with solid tumors. This progress is primarily attributed to the biological characterization of cancers, advancements in testing methodologies, elucidation of the immune microenvironment, and the ability to profile circulating tumor fractions. Integrating these insights promises to continually advance the precision oncology field, fostering better patient outcomes.
Topics: Humans; Biomarkers, Tumor; Medical Oncology; Neoplasms; Precision Medicine; Tumor Microenvironment
PubMed: 38552610
DOI: 10.1016/j.cell.2024.02.041