المؤلفون: Garris, Christopher S. (AUTHOR), Arlauckas, Sean P. (AUTHOR), Kohler, Rainer H. (AUTHOR), Trefny, Marcel P. (AUTHOR), Garren, Seth (AUTHOR), Piot, Cécile (AUTHOR), Engblom, Camilla (AUTHOR), Pfirschke, Christina (AUTHOR), Siwicki, Marie (AUTHOR), Gungabeesoon, Jeremy (AUTHOR), Freeman, Gordon J. (AUTHOR), Warren, Sarah E. (AUTHOR), Ong, SuFey (AUTHOR), Browning, Erica (AUTHOR), Twitty, Christopher G. (AUTHOR), Pierce, Robert H. (AUTHOR), Le, Mai H. (AUTHOR), Algazi, Alain P. (AUTHOR), Daud, Adil I. (AUTHOR), Pai, Sara I. (AUTHOR)

المصدر: Immunity (10747613). Sep2022, Vol. 55 Issue 9, p1749-1749. 1p.

مصطلحات موضوعية: *T cells, *IMMUNOTHERAPY, *CYTOKINES

المؤلفون: Binnewies, Mikhail¹, Mujal, Adriana M.¹, Pollack, Joshua L.², Combes, Alexis J.^1,3, Hardison, Emily A.¹, Barry, Kevin C.^1,3, Tsui, Jessica^1,3, Ruhland, Megan K.¹, Kersten, Kelly¹, Abushawish, Marwan A.², Spasic, Marko⁴, Giurintano, Jonathan P.⁵, Chan, Vincent^1,3, Daud, Adil I.⁴, Ha, Patrick⁵, Ye, Chun J.⁶, Roberts, Edward W.¹, Krummel, Matthew F.^1,3 matthew.krummel@ucsf.edu

المصدر: Cell. Apr2019, Vol. 177 Issue 3, p556-556. 1p.

مصطلحات موضوعية: *DENDRITIC cells, *ANTINEOPLASTIC agents, *T cell differentiation, *CD4 antigen, *CANCER treatment

مستخلص: Differentiation of proinflammatory CD4+ conventional T cells (T conv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ T conv , but then fail to support antitumor CD4+ T conv differentiation. Regulatory T cell (T reg) depletion enhanced their capacity to elicit strong CD4+ T conv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to T reg predicts protective ICOS+ PD-1lo CD4+ T conv phenotypes and survival. Further, in melanoma patients with low T reg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ T conv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ T conv abundance and controls tumor growth. • cDC2 initiate activation but not differentiation of antitumor CD4+ T conv • T reg depletion relieves cDC2 suppression driving antitumor CD4+ T conv differentiation • Human equivalent of mouse cDC2 are present in the tumor and draining lymph node • The balance of human cDC2/T reg in the TME dictates T cell quality and prognosis A subtype of conventional dendritic cells, cDC2, are able to prime CD4+ T cells for antitumor functions and the presence of cDC2 in human cancer samples may serve as a predictive biomarker for survival and response to immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

المؤلفون: Garris, Christopher S.^1,2, Arlauckas, Sean P.^1,3, Kohler, Rainer H.¹, Trefny, Marcel P.^4,5, Garren, Seth¹, Piot, Cécile¹, Engblom, Camilla¹, Pfirschke, Christina¹, Siwicki, Marie^1,2, Gungabeesoon, Jeremy¹, Freeman, Gordon J.⁶, Warren, Sarah E.⁷, Ong, SuFey⁷, Browning, Erica⁸, Twitty, Christopher G.⁸, Pierce, Robert H.⁸, Le, Mai H.⁸, Algazi, Alain P.⁹, Daud, Adil I.⁹, Pai, Sara I.¹⁰

المصدر: Immunity (10747613). Dec2018, Vol. 49 Issue 6, p1148-1148. 1p.

مصطلحات موضوعية: *T cells, *CANCER immunotherapy, *RNA sequencing, *DENDRITIC cells, *CROSSTALK

مستخلص: Summary Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade. Graphical Abstract Highlights • Effective anti-PD-1 anti-tumor responses require IL-12-producing dendritic cells • Anti-PD-1 indirectly activates IL-12 through IFN-γ produced from CD8+ T cells • Agonizing the non-canonical NF-κB pathway enhances dendritic cell IL-12 production • Combining aPD-1 with non-canonical NF-κB agonism enhances checkpoint immunotherapy Anti-PD-1 mAbs can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Garris et al. show that effective anti-PD-1 immunotherapy requires intratumoral dendritic cells (DCs) producing IL-12. Anti-PD-1 indirectly activates DCs through IFN-γ released from drug-activated T cells. Furthermore, agonizing the non-canonical NF-κB pathway activates DCs and enhances aPD-1 therapy in an IL-12-dependent manner. [ABSTRACT FROM AUTHOR]