Let there be oxygen and T cells
Paul R. Walker
Paul R. Walker
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Commentary

Let there be oxygen and T cells

Abstract

The stroma of solid tumors can exclude or limit immune infiltration, or lead to the recruitment of tumor-promoting rather than tumor-attacking immune cells. This finding was reported by Jayaprakash et al. in this issue of the JCI, and it was particularly prominent in the hypoxic zones of tumors in the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer models. A current clinical goal of immune checkpoint blockade (ICB) is to extend its utility to more patients by converting immunologically “cold” tumors that do not provoke a strong immunological response to “hot” tumors that are invaded by swarms of T cells. When the underlying cause is hypoxia linked, the therapeutic combination of simultaneous targeting of hypoxia and immune checkpoints merits exploration in future clinical trials.

Authors

Paul R. Walker

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Figure 1

Combined therapy targeting hypoxia and immune checkpoints reduces immunosuppression within hypoxic zones in TRAMP prostate cancer.

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Combined therapy targeting hypoxia and immune checkpoints reduces immuno...
(A) Untreated TRAMP-C2 tumors exhibit hypoxic zones infiltrated by myeloid-derived suppressor cells (MDSCs) and Tregs, but few T effector (Teff) cells. Vascularization is at low density and aberrant. Suppressive MDSCs can be generated from myeloid progenitor cells. (B) Treatment with the hypoxia-activated prodrug TH-302 combined with anti–CTLA-4/anti–PD-1–blocking antibodies reduces hypoxia and changes the immune infiltrate in residual hypoxic areas. Vessel density increases and vessels display normalized morphology. Fewer arginase-expressing MDSCs can be seen. Generation of these suppressive MDSCs from myeloid progenitor cells is reduced. CD4+ and CD8+ Teff cells infiltrate all areas of the tumor, proliferate, express effector cytokines and granzyme B, and show reduced active caspase-3 expression as a marker of apoptosis. These features are associated with enhanced survival.