Low CD8 T Cell Counts Predict Benefit from Hypoxia-Modifying Therapy in Muscle-Invasive Bladder Cancer.

As hypoxia can drive an immunosuppressive tumour microenvironment and inhibit CD8+ T cells, we investigated if patients with low tumour CD8+ T cells benefitted from hypoxia-modifying therapy.

BCON was a phase III trial that randomised patients with muscle-invasive bladder cancer (MIBC) to radiotherapy alone or with hypoxia-modifying carbogen plus nicotinamide (CON). Tissue microarrays of diagnostic biopsies from 116 BCON patients were stained using multiplex immunohistochemistry (IHC) with the markers CD8, CD4, FOXP3, CD68 and PD-L1, plus DAPI. Hypoxia was assessed using CA9 IHC (n = 111). Linked transcriptomic data (n = 80) identified molecular subtype. Relationships with overall survival (OS) were investigated using Cox proportional hazard models.

High (upper quartile) vs. low CD8 T cell counts associated with a better OS across the whole cohort at 16 years (n = 116; HR 0.47, 95% CI 0.28-0.78, p = 0.003) and also in the radiotherapy alone group (n = 61; HR 0.39, 95% CI 0.19-0.76, p = 0.005). Patients with low CD8+ T cells benefited from CON (n = 87; HR 0.63, 95% CI 0.4-1.0, p = 0.05), but those with high CD8 T cells did not (n = 27; p = 0.95). CA9 positive tumours had fewer CD8+ T cells (p = 0.03). Prognostic significance of low CD8+ T cells in the whole cohort remained after adjusting for clinicopathologic variables. Basal vs. luminal subtype had more CD8+ cells (p = 0.02) but was not prognostic (n = 80; p = 0.26). Exploratory analyses with other immune markers did not improve on findings obtained with CD8 counts.

MIBC with low CD8+ T cell counts may benefit from hypoxia-modifying treatment.

Cancers. 2022 Dec 21*** epublish ***

Vicky Smith, Debayan Mukherjee, Anna Maria Tsakiroglou, Alexander Baker, Hitesh Mistry, Ananya Choudhury, Peter Hoskin, Timothy Illidge, Catharine M L West

Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK., Cancer Research UK Manchester Institute, Manchester M20 4BX, UK., Division of Pharmacy and Optometry, University of Manchester, Manchester M13 9PL, UK.