apyrase and Skin-Neoplasms

Topics: 5'-Nucleotidase; Adenosine; Adenosine Triphosphate; Apyrase; Humans; Immune Tolerance; Immunosuppression Therapy; Sezary Syndrome; Skin Neoplasms; T-Lymphocytes

Topics: 5'-Nucleotidase; Adenosine; Antibody-Dependent Cell Cytotoxicity; Antigens, CD; Apyrase; Cell Proliferation; Humans; Killer Cells, Natural; Sezary Syndrome; Skin Neoplasms

Sézary syndrome (SS) is a rare and aggressive variant of cutaneous T-cell lymphoma. It is characterized by the copresence of CD4+ neoplastic lymphocytes, named Sezary cells, mainly in the blood, lymph nodes, and skin where they induce chronic inflammation that in turn impairs the patient's QOL and fuels neoplastic cells. SS is not readily cured, but immunotherapy is becoming an effective option for this lymphoma. In this study, we investigated, in a large cohort of patients with SS, the expression and function of the immune checkpoint molecule CD39, which degrades proinflammatory extracellular adenosine triphosphate. We showed that the SNP rs10748643 A/G within the ENTPD1 gene coding for the CD39 protein controls its expression level. Patients carrying the A/G‒G/G genotype showed a significantly higher frequency of clonal CD4+CD39+ SS cells than those carrying the A/A genotype. Different from other cancers, high CD39 expression correlates with a better prognosis. Comparing primary G/G with A/A lymphoma cells, we observed that G/G SS cells have a higher ability to degrade adenosine triphosphate, increased apoptotic susceptibility, and upon activation, reduced IL-2 production. Accordingly, CD39 enzymatic inhibition enhances SS cell viability and IL-2 production on activation. These results strongly suggest a special caution for SS treatment with therapeutic inhibitors of CD39.

Topics: Adenosine Triphosphate; Apyrase; Cell Survival; Humans; Immune Checkpoint Proteins; Interleukin-2; Lymphocytes; Prognosis; Quality of Life; Sezary Syndrome; Skin Neoplasms; T-Lymphocytes, Regulatory

Adjuvant immune checkpoint inhibitor (ICI) immunotherapies have significantly reduced the recurrence rate in high-risk patients with stage III melanoma compared with surgery alone. However, 48% of anti-PD-1-treated patients will develop recurrent disease within 4 years. There is a need to identify biomarkers of recurrence after adjuvant ICI to enable identification of patients in need of alternative treatment strategies. As cytotoxic T cells are critical for the antitumor response to anti-PD-1, we sought to determine whether specific subsets were predictive of recurrence in anti-PD-1-treated high-risk patients with stage III melanoma.. Associations with recurrence in patients with stage III melanoma were sought by analyzing resection specimens (n=103) taken prior to adjuvant nivolumab/pembrolizumab±low-dose/low-interval ipilimumab. Multiplex immunohistochemistry was used to quantify intratumoral CD8+ T-cell populations using phenotypical markers CD39, CD103, and PD-1.. With a median follow-up of 19.3 months, 37/103 (36%) of patients had a recurrence. Two CD8+ T-cell subpopulations were significantly associated with recurrence. First, CD39+ tumor-resident memory cells (CD39+CD103+PD-1+CD8+ (CD39+ Trm)) comprised a significantly higher proportion of CD8+ T cells in recurrence-free patients (p=0.0004). Conversely, bystander T cells (CD39-CD103-PD-1-CD8+) comprised a significantly greater proportion of T cells in patients who developed recurrence (p=0.0002). Spatial analysis identified that CD39+ Trms localized significantly closer to melanoma cells than bystander T cells. Multivariable analysis confirmed significantly improved recurrence-free survival (RFS) in patients with a high proportion of intratumoral CD39+ Trms (1-year RFS high 78.1% vs low 49.9%, HR 0.32, 95% CI 0.15 to 0.69), no complete lymph node dissection performed, and less advanced disease stage (HR 2.85, 95% CI 1.13 to 7.19, and HR 1.29, 95% CI 0.59 to 2.82). The final Cox regression model identified patients who developed recurrence with an area under the curve of 75.9% in the discovery cohort and 69.5% in a separate validation cohort (n=33) to predict recurrence status at 1 year.. Adjuvant immunotherapy-treated patients with a high proportion of CD39+ Trms in their baseline melanoma resection have a significantly reduced risk of melanoma recurrence. This population of T cells may not only represent a biomarker of RFS following anti-PD-1 therapy, but may also be an avenue for therapeutic manipulation and enhancing outcomes for immunotherapy-treated patients with cancer.

Topics: Apyrase; Humans; Immunotherapy; Melanoma; Melanoma, Cutaneous Malignant; Programmed Cell Death 1 Receptor; Skin Neoplasms

UVR and immunosuppression are major risk factors for cutaneous squamous cell carcinoma (cSCC). Regulatory T cells promote cSCC carcinogenesis, and in other solid tumors, infiltrating regulatory T cells and CD8

Topics: Adenosine; Apyrase; Carcinoma, Squamous Cell; DNA Damage; DNA Repair; Forkhead Transcription Factors; Humans; Interleukin-27; Memory T Cells; Neoplasm Metastasis; Programmed Cell Death 1 Receptor; Skin Neoplasms; Ultraviolet Rays

Adoptive T cell therapy (ACT) using ex vivo-expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate complete regression of certain human cancers. The impact of TIL phenotypes on clinical success of TIL-ACT is currently unclear. Using high-dimensional analysis of human ACT products, we identified a memory-progenitor CD39-negative stem-like phenotype (CD39

Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Apyrase; CD8-Positive T-Lymphocytes; Female; Humans; Immunotherapy, Adoptive; Lectins, C-Type; Lymphocytes, Tumor-Infiltrating; Melanoma; Mice; Mice, Mutant Strains; Skin Neoplasms

Topics: Antigens, CD; Apyrase; Biomarkers, Tumor; Biopsy, Needle; Case-Control Studies; Flow Cytometry; Humans; Immunohistochemistry; Male; Middle Aged; Neoplastic Cells, Circulating; Prognosis; Reference Values; Sezary Syndrome; Skin Neoplasms; T-Lymphocytes; Tumor Burden

An imbalance of immunosuppressive and cytotoxic cells plays an important role in inhibiting the anti-tumor immune response of the tumor-bearing host. The purpose of this study was to elucidate the involvement of immunosuppressive cells, such as regulatory T cells and CD163+ M2 macrophages as well as cytotoxic cells, such as granulysin-bearing cells and TIA-1+ cells in cutaneous angiosarcoma (AS) by immunohistochemical staining. In addition we evaluated the potencies of bisphosphonate, which was previously reported to suppress the expression of matrix metalloproteinase 9 (MMP-9), as a supportive therapy for AS together with docetaxel in 6 cases of cutaneous AS. These findings suggest that a high number of immunosuppressive cells might be related to the prognosis of AS, and that a combination of docetaxel with bisphosphonate risedronate sodium might be effective for MMP-9-expressing AS.

Topics: Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antigens, Differentiation, T-Lymphocyte; Antineoplastic Agents; Apyrase; Docetaxel; Drug Therapy, Combination; Enzyme Inhibitors; Etidronic Acid; Female; Forkhead Transcription Factors; Hemangiosarcoma; Humans; Macrophages; Male; Matrix Metalloproteinase 9; Poly(A)-Binding Proteins; Receptors, Cell Surface; Risedronic Acid; Skin Neoplasms; T-Cell Intracellular Antigen-1; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Taxoids

Damage to the vasculature may represent an important component of several forms of cancer therapy. Methods for studying the structure and function of the vasculature of experimental mouse tumours are required. In this paper several relatively simple methods are described for the histological examination of the vascular structure of murine tumours. The methods have been applied to cryostat sections of two sarcomas and two carcinomas. Immunoperoxidase staining with polyclonal antibodies to laminin highlights the vascular basement membrane of sarcomas, but has limited use with carcinomas, while the monoclonal antibody MECA-20 is a good marker for the endothelial cells of all vessels in all four tumours tested. The presence of endothelial cells in normal tissues can also be demonstrated by the use of enzyme-histochemical techniques for alkaline phosphatase, 5'-nucleotidase and nucleotide diphosphatase (ADPase), but only one of these methods (ADPase) works consistently in tumours. The relative merits of these methods are discussed and in all cases related to the staining pattern obtained with normal mouse tissues. The significance of these methods for vascular targeting is also discussed.

Topics: Alkaline Phosphatase; Animals; Antibodies, Monoclonal; Apyrase; Basement Membrane; Biomarkers, Tumor; Capillaries; Carcinoma; Endothelium, Vascular; Female; Immunoenzyme Techniques; Laminin; Male; Mice; Mice, Inbred CBA; Neoplasm Transplantation; Sarcoma, Experimental; Skin Neoplasms