Tumour islet Foxp3⁺T-cell infiltration predicts poor outcome in nonsmall cell lung cancer

Abstract

The impact of host immunity on outcome in nonsmall cell lung cancer (NSCLC) is controversial. We examined the relationship between lymphoid infiltration patterns in NSCLC and prognosis.Tumour-and stroma-infiltrating CD3 + , CD8 + and forkhead box P3 (Foxp3) + T-lymphocytes were identified using immunohistochemistry and a novel image analysis algorithm to assess total, cytotoxic and regulatory T-lymphocyte counts, respectively, in 196 NSCLC cases. The median cell count was selected as a cut-point to define patient subgroups and the ratio of the corresponding tumour islet:stroma (TI/S) counts was determined.There was a positive association between overall survival and increased CD8 + TI/S ratio (hazard ratio (HR) for death 0.44, p<0.001) but an inverse relationship between Foxp3 + TI/S ratio and overall survival (HR 4.86, p<0.001). Patients with high CD8 + islet (HR 0.48, p<0.001) and Foxp3 + stromal (HR 0.23, p<0.001) counts had better survival, whereas high CD3 + and CD8 + stromal counts and high Foxp3 + islet infiltration conferred a worse survival (HR 1.55, 2.19 and 3.14, respectively). By multivariate analysis, a high CD8 + TI/S ratio conferred an improved survival (HR 0.48, p=0.002) but a high Foxp3 + TI/S ratio was associated with worse survival (HR 3.91, p<0.001).Microlocalisation of infiltrating T-lymphocytes is a powerful predictor of outcome in resected NSCLC.@ERSpublications Lymphocyte microlocalisation strongly influences survival in lung cancer patients undergoing curative-intent surgery

Foxp3+cells are running the show in patients with surgically resected nonsmall cell lung cancer

“…O'CALLAGHAN et al [1] analysed the micro-localisation of T-cells (CD3 and CD8 positive cells) and regulatory T-cells (Treg; Foxp3-positive cells) in tumour specimens from 196 patients with stage IA-IIIA surgically resected nonsmall cell lung cancer (NSCLC). The authors selected patients who did not receive adjuvant treatment; this is of particular relevance since chemotherapy can modify immune functions [2] and could act as a confounder with respect to outcome.…”

“…This is probably explained by the fact that CD3 allows identification of all T subsets, therefore a mixture of effector and Treg. Very interestingly, O'CALLAGHAN et al [1] have also analysed the relationship between the absolute lymphocytes counts (cells per mm²) and prognosis. As would be expected, a high number of CD8 + cells and low number of Foxp3 + cells in the tumour islets were associated with a significant survival advantage while high number of Foxp3 + cells was associated with a worse outcome.…”

“…This would allow performing subsequent correlative studies between immune infiltrative patterns, response rates and level of immune reactivation (in the surgical piece). Indeed, it would make sense that anti-PD-1 monotherapy or the combination of anti-PD-1 and anti-CTLA-4 antibodies would provide different response rates within the four subsets of tumour types described by O'CALLAGHAN et al [1] (figure 1).…”

The IL-17-Th1/Th17 pathway: an attractive target for lung cancer therapy?

“…These include a human anti-IL-23R monoclonal antibody developed by Astellas [135]; an oral IL-23R peptide antagonist (PTG-200) developed by Protagonist Therapeutics [136], and a bi-specific antiIL23RxCD3 antibody in development by Numab AG [137,138]. Regarding the utility of CD3+ for specific targeting we and others have recently shown high levels of CD3+ T-cells in NCSLC inNCSLCin both the stroma and tumors [139][140][141], suggesting that such a dual targeting approach may be amenable in NSCLC.…”

Cell-mediated immunotherapy for hepatocellular carcinoma

“…For breast cancer, regulatory T cells were increased in peripheral blood and in the tumor microenvironment [34] . For lung cancer, regulatory T cells selectively inhibited host immune response and may have contributed to disease progression [35] . For HCC, CD4 + CD25…”