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. 2022 Feb 22;10(2):e003490. doi: 10.1136/jitc-2021-003490

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© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.

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Increased CD8⁺ T-cell infiltration into tumors after oncolytic immunotherapy is observed in patients with concomitant TIM-3 decrease, which accounts for further improved overall survival. (A) Percentual change in CD8a IHC score following oncolytic adenovirus treatment in six patients with TIM-3 decrease (circle symbols) and five control patients (TIM-3 increase, triangle symbols; TIM-3 data not available, square symbols): ≥2 fold CD8⁺ increase was only observed in patients with concomitant TIM-3 decrease (open circles; p=0.015, Fisher’s exact test). (B) Representative CD8a IHC of liver metastasis biopsies of a colon adenocarcinoma patient C341 before (top) and after oncolytic adenovirus treatment (bottom) presenting a 45-fold increase (+4454.1%) in CD8a⁺ IHC score (brown color). (C) PBMCs collected on the same days as microarray samples were assessed for tumor-associated antigen (survivin) reactive effector cells by IFN-γ ELISPOT. TIM-3 decrease patients showed high baseline effector responses in blood, followed by reduction in circulation and concomitant CD8⁺ TIL increase in tumors on oncolytic virus therapy (A, B), compatible with CD8⁺ T-cell trafficking. Limited numbers of subjects had available PBMC samples (n=6 and n=3 in TIM-3 decrease and increase groups, respectively), which precluded statistical determination. See also online supplemental figure S6 for linear correlation of CD8⁺ redistribution compatible with trafficking phenomenon. (D) Kaplan-Meier analysis of subgroups based on both TIM-3 status and evidence of CD8⁺ influx into tumors: TIM-3 decrease patients who experienced CD8⁺ T-cell influx (open circles in A) survived longer than patients without both of these phenomena (median OS 336 days vs 72 days in combined others, p=0.002, log-rank test). See also online supplemental figure S7 for survival analysis based also on CD8A expression data in patients that lacked CD8a immunohistochemistry data (NA). *P<0.05, **P<0.01. IFN-γ, interferon gamma; IHC, immunohistochemistry; N/A, not available; OS, overall survival; PBMC, peripheral blood mononuclear cell; SFC, spot-forming colonies; TIM-3, T-cell immunoglobulin and mucin domain-3.