Project description:Adaptive immunotherapy including bispecific T cell engagers (TCE) has shown promise in the treatment of various cancers, but clinical responses are heterogeneous and often not durable. As response to TCE is suggested to be independent of tumor recognition and T cell state, molecular determinants or mediators of primary and acquired resistance towards TCE remain poorly understood. Here, we identify conserved behaviors of bone marrow residing CD4+ and CD8+ T cells in multiple myeloma patients undergoing TCE therapy. We show that the bone marrow immune landscape reacts to TCE therapy with cell state-dependent clonal T cell expansion and herewith infer coupling of tumor recognition via MHC-I, T cell exhaustion and clinical response. While we find the abundance of exhausted-like memory CD8+ T cell clones to be associated with clinical response failure, we describe loss of target epitope and MHC class I expression as tumor-intrinsic mechanisms of acquired resistance to TCE.
Project description:Adaptive immunotherapy including bispecific T cell engagers (TCE) has shown promise in the treatment of various cancers, but clinical responses are heterogeneous and often not durable. As response to TCE is suggested to be independent of tumor recognition and T cell state, molecular determinants or mediators of primary and acquired resistance towards TCE remain poorly understood. Here, we identify conserved behaviors of bone marrow residing CD4+ and CD8+ T cells in multiple myeloma patients undergoing TCE therapy. We show that the bone marrow immune landscape reacts to TCE therapy with cell state-dependent clonal T cell expansion and herewith infer coupling of tumor recognition via MHC-I, T cell exhaustion and clinical response. While we find the abundance of exhausted-like memory CD8+ T cell clones to be associated with clinical response failure, we describe loss of target epitope and MHC class I expression as tumor-intrinsic mechanisms of acquired resistance to TCE.
Project description:T cell engagers (TCEs) are transformational oncology therapies but limited in use due to the induction of cytokine release syndrome (CRS). In comparison to T cells, natural killer (NK) cells produce less cytokines upon activation, leading to the exploration of NK cell engagers (NKCEs). However, why NK cells secrete less cytokines such as tumor necrosis factor (TNF) and how NKCEs perform directly against TCEs remain unclear. Here we report that relative to T cells, NK cells have reduced trafficking and processing of TNF. Systematic development and benchmarking studies show that NKCEs can be optimized to engage multiple activating receptors and incorporate the interleukin (IL)-2, thereby increasing their potency and durability. Furthermore, comparative studies of NKCE, IL-2, and TCE therapy in animal tumor models reveal both common and different therapeutic benefits. Our results provide a blueprint for development of multifunctional NKCEs that may serve as an alternative to current TCE therapies.
Project description:Response to tumor- infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+T- myeloid cell networks in melanoma
Project description:Response to tumor- infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+T- myeloid cell networks in melanoma [scTCRseq]
Project description:Response to tumor- infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+T- myeloid cell networks in melanoma [full scRNAseq]
Project description:Response to tumor- infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+T- myeloid cell networks in melanoma [bulk RNAseq]
Project description:Response to tumor- infiltrating lymphocyte adoptive therapy is associated with preexisting CD8+T- myeloid cell networks in melanoma [CD45 scRNAseq]