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Modulating the tumor immune phenotypes by radiotherapy: formulating and validating the combination therapy of radiation, PD-L1, and TIM-3 blockade in colorectal cancer - PubMed

4 hours ago
  • #Immune Checkpoint Inhibitors
  • #Colorectal Cancer
  • #Radiotherapy
  • Colorectal cancers (CRCs) with mismatch repair-proficient (pMMR) and microsatellite stable (MSS) status respond poorly to immune checkpoint inhibitors (ICIs).
  • Radiotherapy (RT) can promote antitumor immunity but may also trigger adaptive immune suppression through checkpoint upregulation.
  • TIM-3 and galectin-9 are broadly expressed in CRC, remaining relatively high in MSS/pMMR tumors compared to other checkpoints.
  • In CT26 tumors, RT increased PD-1 and TIM-3 co-expression on CD8+ T cells and NK cells, while this effect was weaker in MC38 tumors.
  • Combining TIM-3 blockade with RT and PD-L1 blockade showed the most durable antitumor activity in CT26 tumors, improving primary tumor control and abscopal effects.
  • In patient-derived organoid (PDO)-immune co-cultures, pMMR PDOs benefited more from adding TIM-3 blockade to RT+PD-L1 blockade compared to dMMR PDOs.
  • Clinical datasets showed RT-containing treatments increased T-cell infiltration and TIM-3/PD-1 signals, with systemic immune alterations like TIM-3 induction on circulating immune subsets.
  • High expression of HAVCR2 and PDCD1 in pan-cancer cohorts treated with ICIs correlated with immune-activated transcriptional profiles and improved clinical outcomes.
  • TIM-3/PD-L1 is identified as a context-dependent adaptive resistance axis following RT, with the greatest incremental value of TIM-3 blockade observed in MSS/pMMR settings.
  • Combining RT with dual TIM-3/PD-L1 blockade warrants further clinical evaluation for immunotherapy-refractory CRC.