Granzymes expression patterns predict immunotherapy response and identify the heterogeneity of CD8⁺ T cell subsets

BACKGROUND: Recent studies illustrated the effects of granzymes (GZMs) gene alterations on immunotherapy response of cancer patients. Thus, we aimed to systematically analyze the expression and prognostic value of GZMs for immunotherapy in different cancers, and identified heterogeneity of the GZMs expression-based CD8(+) T cell subsets. METHODS: First, we analyzed GZMs expression and prognostic value at pan-cancer level. Meanwhile, we established a GZMs score by using the single-sample gene set enrichment analysis (ssGSEA) algorithm to calculate the enrichment scores (ES) based on a gene set of five GZMs. The potential value of GZMs score for predicting survival and immunotherapy response was evaluated using the tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) algorithm, and we validated it in immunotherapy cohorts. CellChat, scMetabolism, and SCENIC R packages were used for intercellular communication networks, quantifying metabolism activity, and regulatory network reconstruction, respectively. RESULTS: The GZMs score was significantly associated with IPS, TIDE score. Patients with high GZMs score tended to have higher objective response rates of immunotherapy in melanoma and urothelial carcinoma. GZMs expression-based CD8(+) T cell subsets presented heterogeneity in functions, metabolism, intercellular communications, and the tissue-resident memory programs in lung adenocarcinoma (LUAD). The transcription factors RUNX3 and ETS1, which may regulate the expression of GZMs, was found to be positively correlated with the tissue-resident memory T cells-related marker genes. CONCLUSIONS: The higher GZMs score may indicate better response and overall survival (OS) outcome for immunotherapy in melanoma and urothelial carcinoma but worse OS in renal cell carcinoma (RCC). The GZMs score is a potential prognostic biomarker of diverse cancers. RUNX3 and ETS1 may be the potential targets to regulate the infiltration of GZMs expression-based CD8(+) T cell subsets and affect the tissue-resident memory programs in LUAD, which may affect the prognosis of LUAD patients and the response to immunotherapy.