المؤلفون: Santos, Patricia M., Adamik, Juraj, Howes, Timothy R., Du, Samuel, Vujanovic, Lazar, Warren, Sarah, Gambotto, Andrea, Kirkwood, John M., Butterfield, Lisa H.

المساهمون: University of Pittsburgh Cancer Institute, National Cancer Institute, Parker Institute for Cancer Immunotherapy

المصدر: Journal of Experimental Medicine ; volume 217, issue 7 ; ISSN 0022-1007 1540-9538

الوصف: Immune and molecular profiling of CD8 T cells of patients receiving DC vaccines expressing three full-length melanoma antigens (MAs) was performed. Antigen expression levels in DCs had no significant impact on T cell or clinical responses. Patients who received checkpoint blockade before DC vaccination had higher baseline MA-specific CD8 T cell responses but no evidence for improved functional responses to the vaccine. Patients who showed the best clinical responses had low PD-1 expression on MA-specific T cells before and after DC vaccination; however, blockade of PD-1 during antigen presentation by DC had minimal functional impact on PD-1high MA-specific T cells. Gene and protein expression analyses in lymphocytes and tumor samples identified critical immunoregulatory pathways, including CTLA-4 and PD-1. High immune checkpoint gene expression networks correlated with inferior clinical outcomes. Soluble serum PD-L2 showed suggestive positive association with improved outcome. These findings show that checkpoint molecular pathways are critical for vaccine outcomes and suggest specific sequencing of vaccine combinations.

الإتاحة: https://doi.org/10.1084/jem.20191369Test

المؤلفون: Fourcade, Julien, Sun, Zhaojun, Benallaoua, Mourad, Guillaume, Philippe, Luescher, Immanuel F., Sander, Cindy, Kirkwood, John M., Kuchroo, Vijay, Zarour, Hassane M.

المصدر: Journal of Experimental Medicine ; volume 207, issue 10, page 2175-2186 ; ISSN 1540-9538 0022-1007

الوصف: The paradoxical coexistence of spontaneous tumor antigen–specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1–specific CD8+ T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1–specific CD8+ T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1+ NY-ESO-1–specific CD8+ T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3+PD-1+ NY-ESO-1–specific CD8+ T cells are more dysfunctional than Tim-3−PD-1+ and Tim-3−PD-1− NY-ESO-1–specific CD8+ T cells, producing less IFN-γ, TNF, and IL-2. Tim-3–Tim-3L blockade enhanced cytokine production by NY-ESO-1–specific CD8+ T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3–Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1–specific CD8+ T cells upon prolonged antigen stimulation and acted in synergy with PD-1–PD-L1 blockade. Collectively, our findings support the use of Tim-3–Tim-3L blockade together with PD-1–PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.

الإتاحة: https://doi.org/10.1084/jem.20100637Test
https://rupress.org/jem/article-pdf/207/10/2175/1736223/jem_20100637.pdfTest

المؤلفون: Mailliard, Robbie B., Alber, Sean M., Shen, Hongmei, Watkins, Simon C., Kirkwood, John M., Herberman, Ronald B., Kalinski, Pawel

المصدر: The Journal of Experimental Medicine ; volume 202, issue 7, page 941-953 ; ISSN 1540-9538 0022-1007

الوصف: In addition to their cytotoxic activities, natural killer (NK) cells can have immunoregulatory functions. We describe a distinct “helper” differentiation pathway of human CD56+CD3− NK cells into CD56+/CD83+/CCR7+/CD25+ cells that display high migratory responsiveness to lymph node (LN)–associated chemokines, high ability to produce interferon-γ upon exposure to dendritic cell (DC)- or T helper (Th) cell–related signals, and pronounced abilities to promote interleukin (IL)-12p70 production in DCs and the development of Th1 responses. This helper pathway of NK cell differentiation, which is not associated with any enhancement of cytolytic activity, is induced by IL-18, but not other NK cell–activating factors. It is blocked by prostaglandin (PG)E2, a factor that induces a similar CD83+/CCR7+/CD25+ LN-homing phenotype in maturing DCs. The current data demonstrate independent regulation of the “helper” versus “effector” pathways of NK cell differentiation and novel mechanisms of immunoregulation by IL-18 and PGE2.

الإتاحة: https://doi.org/10.1084/jem.20050128Test
https://rupress.org/jem/article-pdf/202/7/941/1719058/jem2027941.pdfTest

المؤلفون: Tatsumi, Tomohide, Kierstead, Lisa S., Ranieri, Elena, Gesualdo, Loreto, Schena, Francesco P., Finke, James H., Bukowski, Ronald M., Mueller-Berghaus, Jan, Kirkwood, John M., Kwok, William W., Storkus, Walter J.

المصدر: The Journal of Experimental Medicine ; volume 196, issue 5, page 619-628 ; ISSN 1540-9538 0022-1007

الوصف: T helper type 1 (Th1)-type CD4+ antitumor T cell help appears critical to the induction and maintenance of antitumor cytotoxic T lymphocyte (CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4+ T cell responses may subvert Th1-type cell-mediated immunity, providing a microenvironment conducive to disease progression. We have recently identified helper T cell epitopes derived from the MAGE-6 gene product; a tumor-associated antigen expressed by most melanomas and renal cell carcinomas. In this study, we have assessed whether peripheral blood CD4+ T cells from human histocompatibility leukocyte antigens (HLA)-DRβ1*0401+ patients are Th1- or Th2-biased to MAGE-6 epitopes using interferon (IFN)-γ and interleukin (IL)-5 enzyme-linked immunospot assays, respectively. Strikingly, the vast majority of patients with active disease were highly-skewed toward Th2-type responses against MAGE-6–derived epitopes, regardless of their stage (stage I versus IV) of disease, but retained Th1-type responses against Epstein-Barr virus– or influenza-derived epitopes. In marked contrast, normal donors and cancer patients with no current evidence of disease tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized responses to MAGE-6 peptides, respectively. CD4+ T cell secretion of IL-10 and transforming growth factor (TGF)-β1 against MAGE-6 peptides was not observed, suggesting that specific Th3/Tr-type CD4+ subsets were not common events in these patients. Our data suggest that immunotherapeutic approaches will likely have to overcome or complement systemic Th2-dominated, tumor-reactive CD4+ T cell responses to provide optimal clinical benefit.

الإتاحة: https://doi.org/10.1084/jem.20012142Test
https://rupress.org/jem/article-pdf/196/5/619/1708428/jem1965619.pdfTest

المؤلفون: Mailliard, Robbie B., Alber, Sean M., Shen, Hongmei, Watkins, Simon C., Kirkwood, John M., Herberman, Ronald B., Kalinski, Pawel

المصدر: Journal of Experimental Medicine; 10/3/2005, Vol. 202 Issue 7, p941-953, 13p, 1 Diagram, 7 Graphs

مصطلحات موضوعية: INTERLEUKINS, KILLER cells, IMMUNOREGULATION, LYMPH nodes, CHEMOKINES, INTERFERONS, DENDRITIC cells, PROSTAGLANDINS E

مستخلص: In addition to their cytotoxic activities, natural killer (NK) cells can have immunoregulatory functions. We describe a distinct "helper" differentiation pathway of human CD56⁺CD3^- NK cells into CD56⁺/CD83⁺/CCR7⁺/CD25⁺ cells that display high migratory responsiveness to lymph node (LN)-associated chemokines, high ability to produce interferon-γ upon exposure to dendritic cell (DC)- or T helper (Th) cell-related signals, and pronounced abilities to promote interleukin (IL)-12p70 production in DCs and the development of Th1 responses. This helper pathway of NK cell differentiation, which is not associated with any enhancement of cytolytic activity, is induced by IL-18, but not other NK cell-activating factors. It is blocked by prostaglandin (PG)E2, a factor that induces a similar CD83⁺/CCR7⁺/CD25⁺ LN-homing phenotype in maturing DCs. The current data demonstrate independent regulation of the "helper" versus "effector" pathways of NK cell differentiation and novel mechanisms of immunoregulation by IL-18 and PGE2. [ABSTRACT FROM AUTHOR]

: Copyright of Journal of Experimental Medicine is the property of Rockefeller University Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)