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Checkpoint blockade immunotherapy is now a first-line treatment option for patients with melanoma. Despite achieving objective responses in about half of patients, the exact immune mechanisms elicited and those required for therapeutic success have not been clearly identified. Insight into these mechanisms is key for improving outcomes in a broader range of cancer patients. We used a murine melanoma model to track responses by different subsets of tumor-infiltrating lymphocytes (TIL) during checkpoint blockade immunotherapy. Tumors from treated mice had increased frequencies of both CD4 and CD8 T cells, which also showed evidence of functional reinvigoration and elevated effector cytokine production after immunotherapy. We predicted that increased T cell numbers and function within tumors reflected either infiltration by new T cells or clonal expansion by a few high-affinity tumor-reactive T cells. To address this, we compared TIL diversity before and after immunotherapy by sequencing the complementarity determining region 3 (CDR3) of all T cell receptor beta (TCRβ) genes. While checkpoint blockade effectively slowed tumor progression and increased T cell frequencies, the diversity of intratumoral T cells remained stable. This was true when analyzing total T cells and when focusing on smaller subsets of effector CD4 and CD8 TIL as well as regulatory T cells. Our study suggests that checkpoint blockade immunotherapy does not broaden the T cell repertoire within murine melanoma tumors, but rather expands existing T cell populations and enhances effector capabilities.
This article was published in the following journal.
Name: Cancer immunology, immunotherapy : CII
An improved understanding of the anti-tumor CD8 T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effecto...
Immune checkpoint inhibitors are currently tested in different combinations in patients with advanced hepatocellular carcinoma (HCC). Nivolumab, an anti-PD-1 agent, has gained approval in the second-l...
T lymphocyte-mediated immune responses in the heart are potentially dangerous because they can interfere with the electromechanical function. Furthermore, the myocardium has limited regenerative capac...
Checkpoint blockade mediates a proliferative response of tumor-infiltrating CD8 T lymphocytes (TILs). The origin of this response has remained elusive because chronic activation promotes terminal diff...
Colorectal cancer can be categorized into two major molecular subtypes according to the status of their DNA proofreading and repair machinery. The DNA repair status of tumor cells plays a major role i...
The purpose of this study is to determine the effectiveness of combining immune checkpoint blockade therapy with standard chemotherapy. People who usually have this are treated with 3 cycl...
This is a phase IB/II trial that allows us to examine feasibility and safety of checkpoint blockade (aPD1 with or without aCTLA4) neoadjuvant to standard of care (SOC) in advanced stage he...
First-line treatment of locally advanced HNSCC with double checkpoint blockade and radiotherapy dependent on intratumoral CD8+ T cell Infiltration.
This study is a prospective phase II, single arm mono-institutional study conducted in Queen Mary Hospital (Hong Kong) assessing the efficacy and safety of the sequential administration of...
Immune checkpoint inhibitors (ICI) might induce inflammatory potentially serious and even lethal immune related Adverse Events (irAEs). Diarrhea and/or colitis are ones of the most frequen...
A serine/threonine-specific protein kinase which is encoded by the CHEK1 gene in humans. Checkpoint kinase 1 (also known as Chk1) coordinates DNA damage response and cell cycle checkpoint response. Under these conditions, activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death, to prevent damaged cells from progressing through the cell cycle.
A replication-defective strain of Murine leukemia virus (LEUKEMIA VIRUS, MURINE) capable of transforming lymphoid cells and producing a rapidly progressing lymphoid leukemia after superinfection with FRIEND MURINE LEUKEMIA VIRUS; MOLONEY MURINE LEUKEMIA VIRUS; or RAUSCHER VIRUS.
A replication-defective murine sarcoma virus (SARCOMA VIRUSES, MURINE) capable of transforming mouse lymphoid cells and producing erythroid leukemia after superinfection with murine leukemia viruses (LEUKEMIA VIRUS, MURINE). It has also been found to transform cultured human fibroblasts, rat liver epithelial cells, and rat adrenocortical cells.
Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade.
A group of replication-defective viruses, in the genus GAMMARETROVIRUS, which are capable of transforming cells, but which replicate and produce tumors only in the presence of Murine leukemia viruses (LEUKEMIA VIRUS, MURINE).
Allergies Automimmune Disease Human Papillomavirus (HPV) Immunology Vaccine Immunology is the study of immunity and the defence mechanisms of the body. A greater understanding of immunology is needed to develop vaccines, understand ...
Melanoma is a highly malignant tumor of melanin-forming cells (melanocytes) There are most commonly found in the skin (resulting from sunlight exposure), but also in the eyes and mucous membranes. Metastasis to other regions of the body is also common....