Reduced CTL motility and activity in avascular tumor areas

Yoav Manaster, Zohar Shipony, Anat Hutzler, Masha Kolesnikov, Camila Avivi, Bruria Shalmon, Iris Barshack, Michal J. Besser, Tali Feferman, Guy Shakhar

Research output: Contribution to journalArticlepeer-review

Abstract

Patchy infiltration of tumors by cytotoxic T cells (CTLs) predicts poorer prognosis for cancer patients. The factors limiting intratumoral CTL dissemination, though, are poorly understood. To study CTL dissemination in tumors, we histologically examined human melanoma samples and used mice to image B16-OVA tumors infiltrated by OT-I CTLs using intravital two-photon microscopy. In patients, most CTLs concentrated around peripheral blood vessels, especially in poorly infiltrated tumors. In mice, OT-I CTLs had to cluster around tumor cells to efficiently kill them in a contact-and perforin-dependent manner and cytotoxicity was strictly antigen-specific. OT-I CTLs as well as non-specific CTLs concentrated around peripheral vessels, and cleared the tumor cells around them. This was also the case when CTLs were injected directly into the tumors. CTLs crawled rapidly only in areas within 50 µm of flowing blood vessels and transient occlusion of vessels immediately, though reversibly, stopped their migration. In vitro, oxygen depletion and blockade of oxidative phosphorylation also reduced CTL motility. Taken together, these results suggest that hypoxia limits CTL migration away from blood vessels, providing immune-privileged niches for tumor cells to survive. Normalizing intratumoral vasculature may thus synergize with tumor immunotherapy.

Original languageEnglish
Pages (from-to)1287-1301
Number of pages15
JournalCancer Immunology, Immunotherapy
Volume68
Issue number8
DOIs
StatePublished - 1 Aug 2019

Keywords

  • CTLs
  • Cell motility
  • Hypoxia
  • Intravital imaging
  • Tumor immunotherapy
  • Tumor vasculature

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