Exogenous signaling repairs defective T cell signaling inside the tumor microenvironment for better immunity
Casey Moore, Joonbeom Bae, Longchao Liu, Huiyu Li, Yang-Xin Fu, Jian Qiao
Casey Moore, Joonbeom Bae, Longchao Liu, Huiyu Li, Yang-Xin Fu, Jian Qiao
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Research Article Immunology Oncology

Exogenous signaling repairs defective T cell signaling inside the tumor microenvironment for better immunity

Abstract

It is known that tumor-reactive T cells are initially activated in the draining lymph node, but it is not well known whether and how tumor-infiltrating lymphocytes (TILs) are reactivated in the tumor microenvironment (TME). We hypothesize that defective T cell receptor (TCR) signaling and cosignals in the TME limit T cell reactivation. To address this, we designed a mesenchymal stromal cell–based delivery of local membrane-bound anti-CD3 and/or cosignals to explore their contribution to reactivate T cells inside the TME. Combined anti-CD3 and CD40L rather than CD80 led to superior antitumor efficacy compared with either alone. Mechanistically, TCR activation of preexisting CD8+ T cells synergized with CD40L activation of DCs inside the TME for optimum tumor control. Exogenous TCR signals could better reactivate TILs that then exited to attack distal tumors. This study supplies further evidence that TCR signaling for T cell reactivation in the TME is defective but can be rescued by proper exogenous signals.

Authors

Casey Moore, Joonbeom Bae, Longchao Liu, Huiyu Li, Yang-Xin Fu, Jian Qiao

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Figure 5

IL-12 is required for CD40-mediated T cell immunity.

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IL-12 is required for CD40-mediated T cell immunity. (A) C57BL/6J mice w...
(A) C57BL/6J mice were inoculated with 1 × 106 MC38 tumor cells and treated peritumorally (p.t.) with 1 × 106 MSC or MSC-CD3-CD40L on days 11, 14, and 17 and treated with 200 μg each αB7.1/αB7.2 antibody twice weekly starting 1 day before treatment. (B) MSC were cocultured with BMDC at a 1:5 ratio for 24 hours with addition of α-CD40L or α–IL-12. Supernatant from MSC-BMDC coculture was transferred 1:1 into wells of OT-I T cells preactivated by α-CD3 coating for 24 hours. IFN-γ in the supernatant was measured 24 hours after supernatant transfer. (C) MSC, BMDC, and OT-I T cells were cocultured at a 1:1:10 ratio with OVA protein and α–IL-12 blocking antibody for 48 hours, and IFN-γ in the supernatant was measured by cytometric bead array (CBA). (D) C57BL/6J IL-12Rβ–/– mice were inoculated with 1 × 106 MC38 tumor cells and treated peritumorally (p.t.) with 1 × 106 MSC or MSC-CD3-CD40L on days 11, 14, and 17. Data are presented as mean ± SEM from a representative experiment (n = 5 [A and D] and n = 3 [B and C]) of 2–3 independent experiments. Statistical analysis was performed using 2-way ANOVA (A–D) with Holm-Šidák multiple comparisons test (B and C). ****P ≤ 0.0001, **P ≤ 0.01, *P ≤ 0.05.