The positive prognostic effect of stromal CD8+ tumor-infiltrating T cells is restrained by the expression of HLA-E in non-small cell lung carcinoma

Abstract

INTRODUCTIONTumor-infiltrating CD8+ T cells are associated with improved clinical outcomes in non-small cell lung cancer (NSCLC). Here we studied their prognostic effect in the context of the expression of HLA molecules that are key in tumor recognition (HLA-A, B and C) or suppression of immunity (HLA-E) as this is still unknown.METHODSTumor tissue of 197 patients with resected pulmonary adenocarcinoma was analyzed for the presence of CD8+ T cells and the expression of β2-microglobulin, HLA-A, HLA-B/C and HLA-E. The relation of these parameters with overall survival (OS) was assessed.RESULTSLoss and low expression of HLA-A or HLA-B/C was found in 44% and 75% of cases respectively. A high CD8+ tumor infiltration was strongly associated with clinical benefit only when the tumors retained good expression of HLA-A and HLA-B/C (p=0.004). In addition, more than 70% of the tumors were found to display a high expression of HLA-E. The expression of HLA-E by tumor cells was an independent negative prognostic factor for OS (p=0.031). Importantly, a dense stromal CD8+ T cell infiltration was strongly associated with improved OS only in HLA-E negative tumors (p=0.005) and its prognostic effect was completely abolished when tumors highly expressed HLA-E (p=0.989).CONCLUSIONSCD8+ T cell infiltration strongly contributes to a better prognosis in NSCLC when the tumor cells retain the expression of classical HLA class I and do not express HLA-E. Therefore, analysis of HLA-A, -B/C and HLA-E expression should be included as biomarkers to predict the response to immunotherapy.

NKG2A Blockade Potentiates CD8 T Cell Immunity Induced by Cancer Vaccines

“…We and others reported a negative correlation of HLA-E on the overall survival of cancer patients (Talebian Yazdi et al, 2016, Gooden et al, 2011, van Esch et al, 2014, Seliger et al, 2016, Andersson et al, 2016, Silva et al, 2011); in particular, the beneficial effect of high CD8 T cell counts within tumor was mitigated by high protein expression of HLA-E (Talebian Yazdi et al, 2016, Gooden et al, 2011). These findings suggested that NKG2A receptor expression on tumor-infiltrating lymphocytes might hamper their function by interaction with HLA-E in the microenvironment.…”

“…HLA-E is ubiquitously expressed at low levels, but very high expression can be found on trophoblasts and ductal epithelial cells in immune-privileged tissues like placenta and testis, respectively. In cancers, HLA-E is frequently overexpressed compared to their non-transformed counterparts, including melanoma and carcinomas of lung, cervix, ovarium, vulva and head/neck (Talebian Yazdi et al, 2016, Gooden et al, 2011, van Esch et al, 2014, Seliger et al, 2016, Andersson et al, 2016, Silva et al, 2011). The physiological function of HLA-E is to present ‘self’ peptides derived from other HLA class I molecules (DeCloux et al, 1997, Kraft et al, 2000, O’Callaghan et al, 1998) and to limit autoimmune reactivity.…”

In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target

“…The function of Qa-1b/HLA-E in tumour immunity has been unclear, because it can bind to both activating and inhibitory receptors expressed by T cells and NK cells 16,22 , and because it has been variously reported to be associated with good or bad clinical outcomes 23,24 . Loss of function of Qa-1b may increase the immune response to tumours by de-repression of T- or NK-cell function 25,26 or by limiting the stimulation of CD8 + T regulatory cells 27 , either of which would make blockade of HLA-E an attractive immunotherapeutic approach.…”

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

“…The results of several studies have already shown that occurrence of autoimmunity, a systemic chronic inflammation profile, as well as the level of tumor infiltration by different lymphocyte subsets and macrophages, may indeed predict the outcome of patients with different disease including non small cell lung cancer (NSCLC), colorectal carcinoma (CRC), breast cancer, melanoma and other malignant diseases. [16][17][18][19][20][21][22][23][24][25] In particular, the results of previous studies by our group showed that primary tumor infiltration by immune-regulatory T cells (CD25 , namely T cm ) are associated to a prolonged PFS and OS in patients with metastatic colorectal carcinoma undergone frontline chemotherapy. [26][27][28] On these bases, we investigated whether infiltration of the primary tumor by different lymphocyte subsets may predict the outcome of PC patients.…”