CD103+ tumor-infiltrating lymphocytes are tumor-reactive intraepithelial CD8+ T cells associated with prognostic benefit and therapy response in cervical cancer

Abstract

Human papilloma virus (HPV)-induced cervical cancer constitutively expresses viral E6/E7 oncoproteins and is an excellent target for T cell-based immunotherapy. However, not all tumor-infiltrating T cells confer equal benefit to patients, with epithelial T cells being superior to stromal T cells.To assess whether the epithelial T cell biomarker CD103 could specifically discriminate the beneficial antitumor T cells, association of CD103 with clinicopathological variables and outcome was analyzed in the TCGA cervical cancer data set (n = 304) and by immunohistochemistry (IHC) in an independent cohort (n = 460). Localization of CD103+ cells in the tumor was assessed by immunofluorescence. Furthermore, use of CD103 as a response biomarker was assessed in an in vivo E6/E7+ tumor model.Our results show that CD103 gene expression was strongly correlated with cytotoxic T cell markers (e.g. CD8/GZMB/PD1) in the TCGA series. In line with this, CD103+ cells in the IHC series co-expressed CD8 and were preferentially located in cervical tumor epithelium. High CD103+ cell infiltration was strongly associated with an improved prognosis in both series, and appeared to be a better predictor of outcome than CD8. Interestingly, the prognostic benefit of CD103 in both series seemed limited to patients receiving radiotherapy. In a preclinical mouse model, HPV E6/E7-targeted therapeutic vaccination in combination with radiotherapy increased the intratumoral number of CD103+ CD8+ T cells, providing a potential mechanistic basis for our results.In conclusion, CD103 is a promising marker for rapid assessment of tumor-reactive T cell infiltration of cervical cancers and a promising response biomarker for E6/E7-targeted immunotherapy.

NKG2A Blockade Potentiates CD8 T Cell Immunity Induced by Cancer Vaccines

“…Indeed, NKG2A expression was recently also reported on T cells from normal lung tissues, where they were poised for rapid responsiveness (Hombrink et al, 2016). In combination with the fact that CD103 + T cells have been associated with good clinical prognosis in multiple cancers (Webb et al, 2014b, Komdeur et al, 2017, Wang et al, 2016, Bosmuller et al, 2016, Webb et al, 2014a), these findings portrays the NKG2A-positive CD8 T cell subset as tissue-residing lymphocytes with immediate effector functions kept in check by their inhibiting receptors, such as NKG2A.…”

Tissue‐resident memory T cells in tissue homeostasis, persistent infection, and cancer surveillance

“…Tumor‐associated human CD8 + T cells with a CD69 + CD103 + T RM phenotype have been described in patients suffering from a broad variety of cancers, including urothelial, colorectal, ovarian, endometrial, cervical and lung cancer, as well as glioblastoma and melanoma . Often these cells are confined to epithelial compartments within or around tumors and their transcriptional profile resembles that of T RM cells in murine tissues, meaning that tumor‐associated CD8 + CD69 + CD103 + T cells are likely bona fide T RM cells . Intriguingly, strong accumulation of these T RM cells or their transcriptional marks, respectively, correlates with prolonged survival in a spectrum of patients and has been shown to be a better prognostic marker than total CD8 + T cell counts in some cancers .…”

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

“…Reports have demonstrated that a high number of tumour‐infiltrating T RM cells is linked to improved prognosis in patients with urinary bladder, lung, cervical and ovarian cancers [7, 8, 9, 10]. The improved prognosis is due to the capacity of T RM cells to produce IFN‐γ upon in‐situ antigen recognition [11], resulting in the recruitment of circulating T cells from the blood [12].…”