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Preprint WatchModerateAugust 31st, 2026

Higher T-cell density in primary prostate cancer is associated with reduced fraction of CD8 effector cells and increased TIGIT

Awad, S.; Calagua, C.; Voznesensky, O.; Abdelkader, S.; Mohanna, R.; Kissick, H.; Signoretti, S.; Einstein, D.; Balk, S.

Higher T-cell density in untreated primary prostate cancer is accompanied by a reduced fraction of CD8 effector cells and increased TIGIT, proposed as a rationale for checkpoint blockade in a tumour usually treated as immunologically cold.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The preprint reads increased TIGIT alongside a depleted CD8 effector fraction as evidence that primary prostate cancer contains infiltrates worth targeting with checkpoint blockade. Claidex holds two Phase 3 TIGIT terminations, both coded efficacy_failure and both in non-small cell lung cancer: ociperlimab-tigit-advantig-302-nsclc-class-failure and tiragolumab-tigit-adjuvant-nsclc-phase3-class-efficacy-failure. Both selected patients on PD-L1 expression rather than on TIGIT abundance, and neither improved outcomes. The observation that TIGIT marks a dysfunctional rather than a productive infiltrate is compatible with two readings. TIGIT may identify tumours whose T-cell compartment is already exhausted, which is a biomarker claim, or it may mark a pathway whose blockade does not restore function, which is what the two Phase 3 results indicate. The flag is moderate because a new indication is being proposed for a mechanism carrying two large negative trials, and because the preprint does not test whether TIGIT abundance predicts response to blockade.

Abstract excerpt

A subset of untreated primary prostate cancer (PCa) contain substantial focal T-cell infiltrates, but whether these reflect antitumor responses that could potentially be enhanced by immune checkpoint blockade (ICB) remains unclear. We used immunohistochemistry, immunofluorescence, whole-slide spatial analysis, bulk RNA sequencing, and immune-cell deconvolution to characterize immune infiltrates in untreated primary PCa. Absolute CD8 T-cell density generally increased with total CD3 T-cell density, but the CD8/CD3 ratio decreased as overall T-cell density increased, indicating a preferential increase in CD4 T cells. Highly infiltrated tumors also had lower GZMB abundance relative to CD8 T-cell abundance. Multiplex analysis showed trends toward greater TIM3 and LAG3 expression among PD1CD8 T cells and increased regulatory T-cell features in highly infiltrated tumors. TIGIT cell density and the TIGIT/CD3 ratio increased with T-cell infiltration, whereas PD1/CD3 was not associated with overall CD3 T-cell density. Both TIGIT/CD3 and PD1/CD3 ratios were enriched within lymphoid aggregates compared with matched tumor and benign regions, consistent with these structures being checkpoint-rich immune niches. Transcriptomic analyses supported a shift in relative immune composition toward CD4 T cells and selective increases in immune checkpoints. Together these findings suggest that effective immune responses in a subset of primary PCa with increased T-cell infiltration are being repressed by several mechanisms and may respond to therapies targeting specific immunosuppressive mechanisms.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.