TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8⁺T cell and XCR1⁺dendritic cell spatial co-localization

Abstract

BackgroundT cell immunoglobulin and mucin domain containing−3 (TIM-3) blocking antibodies are currently being evaluated in clinical trials for solid and hematological malignancies. Despite its identification on T cells, TIM-3 is predominantly expressed by myeloid cells, including XCR1+ type I conventional dendritic cells (cDC1s). We have recently shown that TIM-3 blockade promotes expression of CXCR3 chemokine ligands by tumor cDCs, but how this drives a CD8+ T cell-dependent response to therapy is unclear.MethodsT cell infiltration, effector function, and spatial localization in relation to XCR1+ cDC1s were evaluated in a murine orthotopic mammary carcinoma model during response to TIM-3 blockade and paclitaxel chemotherapy. Mixed bone marrow chimeras and diphtheria toxin depletion were used to determine the role of specific genes in cDC1s during therapeutic responses.ResultsTIM-3 blockade increased interferon-γ expression by CD8+ T cells without altering immune infiltration. cDC1 expression of CXCL9, but not CXCL10, was required for response to TIM-3 blockade. CXCL9 was also necessary for the increased proximity observed between CD8+ T cells and XCR1+ cDC1s during therapy. Tumor responses were dependent on cDC1 expression of interleukin-12, but not MHCI.ConclusionsTIM-3 blockade increases exposure of intratumoral CD8+ T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.

Longitudinal analysis of DC subsets in patients with ovarian cancer: Implications for immunotherapy

“…Recently, direct reprogramming from embryonic fibroblast has resulted in successful generation of human cDC1 (48) paving a new way for vaccination strategies. Of relevance, mechanisms of action and the clinical efficacy of multiple checkpoint inhibitors and adoptive cell therapy also depend on DC function and localization (8,14,15,(49)(50)(51)(52). Thus, our observations are not only important for the efficacy of vaccine strategies but also for other immunotherapies and even other treatments that likely rely on DC functionality.…”

Decoupled neoantigen cross-presentation in tumors with high intratumor heterogeneity reduces dendritic cell activation to limit anti-tumor immunity

“…While our observations are predominately focused on the induction of a NeoAg T cell response, cDC1 mediated restimulation of effector T cells is also a critical feature in the tumor microenvironment 66, 67 . However, within the tumor the expression patterns of NeoAg will likely be even more critical, as spatial analysis of the tumor suggest the formation of areas of clonal growth resulting in patches of NeoAg expression 68–70 .…”

Mature dendritic cells enriched in immunoregulatory molecules (mregDCs): A novel population in the tumour microenvironment and immunotherapy target

“… 37 Furthermore, TIM‐3 inhibition was found to cause cDC1‐like mregDCs to take up more tumour antigen and activate the cGAS–STING pathway, 83 inducing the release of CXCL9 and IL‐12 from mregDCs and encouraging CD8 + T‐cell colocalisation with DCs to enhance antitumour immunity. 84 The bispecific antibody ABL501, which targets both LAG‐3 and PD‐L1, promotes mregDC interaction with T cells and consequently induces efficient CD8 + T‐cell responses. 85 More importantly, blocking the mregDC and Treg interaction could promote their communication with effector T cells.…”

“…Moreover, when anti‐TIM‐3 and anti‐PD‐L1 treatments were combined, the tumour burden was significantly reduced 37 . Furthermore, TIM‐3 inhibition was found to cause cDC1‐like mregDCs to take up more tumour antigen and activate the cGAS–STING pathway, 83 inducing the release of CXCL9 and IL‐12 from mregDCs and encouraging CD8 + T‐cell colocalisation with DCs to enhance antitumour immunity 84 . The bispecific antibody ABL501, which targets both LAG‐3 and PD‐L1, promotes mregDC interaction with T cells and consequently induces efficient CD8 + T‐cell responses 85 .…”