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The tumor microenvironment presents physical, immunologic, and metabolic barriers to durable immunotherapy responses. We have recently described roles for both T cell metabolic insufficiency as well as tumor hypoxia as inhibitory mechanisms which prevent T cell activity in murine tumors, but whether intratumoral T cell activity or response to immunotherapy vary between patients as a function of distinct metabolic profiles in tumor cells remains unclear. Here we show that metabolic derangement can vary widely in both degree and type in patient-derived cell lines and in ex vivo analysis of patient samples, such that some cells demonstrate solely deregulated oxidative or glycolytic metabolism. Further, deregulated oxidative, but not glycolytic, metabolism was associated with increased generation of hypoxia upon implantation into immunodeficient animals. Generation of murine single cell melanoma cell lines that lacked either oxidative or glycolytic metabolism showed that elevated tumor oxygen consumption was associated with increased T cell exhaustion and decreased immune activity. Further, melanoma lines lacking oxidative metabolism were solely responsive to anti-PD1 therapy among those tested. Prospective analysis of patient samples immunotherapy revealed that oxidative, but not glycolytic, metabolism was associated with progression on PD-1 blockade. Our data highlight a role for oxygen as a crucial metabolite required for the tumor-infiltrating T cells to differentiate appropriately upon PD-1 blockade, and suggesting tumor oxidative metabolism may be a target to improve immunotherapeutic response.
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Name: JCI insight
Immunotherapy may be an effective way to prevent postoperative recurrence of renal cell carcinoma. Streptavidin-interleukin-2 (SA-IL-2) surface-modified tumor cell vaccine developed through our protei...
Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify f...
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...
Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusi...
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...
This phase II trial studies how well pembrolizumab, ipilimumab, and aspirin work in treating patients with melanoma that has spread to other places in the body or cannot be removed by surg...
The purpose of this study is to investigate the safety, side effects, and benefits of tumor- infiltrating lymphocytes (TILs) when they are given with the drug nivolumab. Nivolumab is a typ...
A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After Programmed Cell Death Protein 1 (PD1) Blockade
This is a single center, phase I pilot study of sequential ONCOS-102 and pembrolizumab in patients with advanced or unresectable melanoma progressing after PD1 blockade. The primary object...
RATIONALE: Vaccines made from a person's white blood cells and a donor's tumor cells may help the body build an effective immune response to kill tumor cells. PURPOSE: This phase II trial...
The goals of this protocol are 1) to investigate the safety and tolerability of neoadjuvant X4P-001 in combination with Keytruda® (pembrolizumab) in patients with resectable melanoma, and...
Form of adoptive transfer where cells with antitumor activity are transferred to the tumor-bearing host in order to mediate tumor regression. The lymphoid cells commonly used are lymphokine-activated killer (LAK) cells and tumor-infiltrating lymphocytes (TIL). This is usually considered a form of passive immunotherapy. (From DeVita, et al., Cancer, 1993, pp.305-7, 314)
Experimentally induced tumor that produces MELANIN in animals to provide a model for studying human MELANOMA.
An unpigmented malignant melanoma. It is an anaplastic melanoma consisting of cells derived from melanoblasts but not forming melanin. (Dorland, 27th ed; Stedman, 25th ed)
Lymphocytes that show specificity for autologous tumor cells. Ex vivo isolation and culturing of TIL with interleukin-2, followed by reinfusion into the patient, is one form of adoptive immunotherapy of cancer.
A cell adhesion molecule of the immunoglobulin superfamily that is expressed by ENDOTHELIAL CELLS where it functions to stabilize INTERCELLULAR JUNCTIONS. It is also highly expressed by melanoma tumor cells and may facilitate their METASTASIS.
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....