Intratumoral CXCL13CD8T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma.

BACKGROUND

Chemokine (C-X-C motif) ligand 13 (CXCL13) was known as a selective chemotaxis for B cells, a product of follicular helper CD4T cells (T) and a contributor to tertiary lymphoid structures (TLS). Although secretion and function of CXCL13 produced by T have been deeply explored, the immune function and prognostic significance of CXCL13 secreted by CD8T cells still remain unrevealed. This study aims to investigate the clinical merit of CXCL13CD8T cells in clear cell renal cell carcinoma (ccRCC).

METHODS

We analyzed prognostic value and immune contexture that associated with CXCL13CD8T cells infiltration level in a total of 755 patients from Zhongshan Hospital cohort (n=223) and The Cancer Genome Atlas cohort (n=532). In vitro analyses were conducted on 42 samples of resected tumor tissue from Zhongshan Hospital in order to detect the immune status of CXCL13CD8T cells and total CD8T cells. Immunohistochemistry (IHC) and flow cytometry were applied to characterize immune cells and portray the tumor microenvironment (TME) in ccRCC.

RESULTS

Intratumoral CXCL13CD8T cells abundance was associated with inferior overall survival and disease-free survival. CXCL13CD8T cells possessed higher level of immune checkpoints like programmed cell-death protein 1 (PD-1), T-cell immunoglobulin mucin 3 (Tim-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), higher Ki-67 expression and lower tumor necrosis factor α (TNF-α), interferon γ (IFN-γ) expression. Total CD8T cells in high-level CXCL13CD8T cells infiltration subgroup exhibited elevated exhausted markers (PD-1, Tim-3, TIGIT) and descended activated markers (TNF-α, IFN-γ) without quantity variance. Furthermore, the abundance of intratumoral CXCL13CD8T cell was correlated with immunoevasive TME accompanied by increased T helper 2 cells, tumor-associated macrophages, Foxp3 regulatory T cells, TLS and decreased natural killer cells, GZMB cells.

CONCLUSIONS

Intratumoral CXCL13CD8T cells infiltration indicated inferior clinical outcome in patients with ccRCC. CXCL13CD8T cells possessed increased exhausted markers, decreased effector molecules and better proliferation ability. CXCL13CD8T cells abundance impaired total CD8T cells' immune function. Intratumoral CXCL13CD8T cells abundance was associated with immunoevasive contexture. The abundance of CXCL13CD8T cells was an independent prognosticator and a potential immunotherapeutic target marker for ccRCC treatment.