Limited Predictive or Prognostic Role of Tumor-Infiltrating Tissue-Resident Memory CD8 T Cells in Patients with Hepatocellular Carcinoma Receiving Immunotherapy

SIMPLE SUMMARY: Total tumor-infiltrating CD8 T cells inconsistently correlate with the efficacy of immune checkpoint blockade (ICB) in hepatocellular carcinoma. Tumor-infiltrating CD8 tissue-resident memory T cells (T(RM)) are considered a surrogate of tumor-specific T cells and correlated better with survival in patients with melanoma, non–small-cell lung cancer, head and neck cancer or bladder cancer who received ICB. However, in this study, compared with total tumor-infiltrating CD8 T cells, tumor-infiltrating CD8 T(RM) cells failed to provide additional advantages in predicting the efficacy of ICB-based immunotherapy in patients with hepatocellular carcinoma. ABSTRACT: Purpose: Tumor-infiltrating tissue-resident memory CD8 T cells (CD8 T(RM); CD103+ CD8+) are considered tumor-specific and may correlate better with the tumor response to immune checkpoint blockade (ICB). This study evaluated the association of tumor-infiltrating CD8 T(RM) and their subsets with the efficacy of immunotherapy in patients with advanced hepatocellular carcinoma (HCC). Experimental Design: Consecutive HCC patients who received ICB in prospective trials were analyzed. Formalin-fixed paraffin-embedded tumor sections were stained for DAPI, CD8, CD103, CD39, programmed cell death-1 (PD-1), and programmed cell death ligand 1 (PD-L1) using a multiplex immunohistochemical method. The densities of CD8 T cells, CD8 T(RM), and CD39+ or PD-L1+ subsets of CD8 T(RM) were correlated with tumor response and overall survival (OS). Results: A total of 73 patients were identified, and 48 patients with adequate pretreatment tumor specimens and complete follow-up were analyzed. A median of 32.7% (range: 0–92.6%) of tumor-infiltrating CD8 T cells were T(RM). In subset analyses, 66.6% ± 34.2%, 69.8% ± 33.4%, and 0% of CD8 T(RM) cells coexpressed CD39, PD-L1, and PD-1, respectively. The objective response rates for CD8 T cell-high, CD8 T(RM)-high, CD39+ CD8 T(RM)-high, and PD-L1+ CD8 T(RM)-high groups were 41.7%, 37.5%, 37.5%, and 29.2%, respectively. Patients with CD8 T cell-high, but not those with CD8 T(RM)-high, CD39+ CD8 T(RM)-high, or PD-L1+ CD8 T(RM)-high, tumors, had significantly prolonged OS (p = 0.0429). Conclusions: Compared with total tumor-infiltrating CD8 T cells, tumor-infiltrating CD8 T(RM) or their subsets failed to provide additional advantages in predicting the efficacy of immunotherapy for HCC.