IL-18 receptor marks functional CD8⁺ T cells in non-small cell lung cancer

Abstract

IL-18 is an inflammasome-related cytokine, member of the IL-1 family, produced by a wide range of cells in response to signals by several pathogen-or damage-associated molecular patterns. It can be highly represented in tumor patients, but its relevance in human cancer development is not clear. In this study, we provide evidence that IL-18 is principally expressed in tumor cells and, in concert with other conventional Th1 cell-driven cytokines, has a pivotal role in establishing a pro-inflammatory milieu in the tumor microenvironment of human non-small cell lung cancer (NSCLC). Interestingly, the analysis of tumor-infiltrating CD8C T cell populations showed that (i) the relative IL-18 receptor (IL-18R) is significantly more expressed by the minority of cells with a functional phenotype (T-bet C Eomes C ), than by the majority of those with the dysfunctional phenotype T-bet ¡ EomesC generally resident within tumors; (ii) as a consequence, the former are significantly more responsive than the latter to IL-18 stimulus in terms of IFNg production ex vivo; (iii) PD-1 expression does not discriminate these two populations. These data indicate that IL-18R may represent a biomarker of the minority of functional tumor-infiltrating CD8 C T cells in adenocarcinoma NSCLC patients. In addition, our results lead to envisage the possible therapeutic usage of IL-18 in NSCLC, even in combination with other checkpoint inhibitor approaches.

Wnt3a Neutralization Enhances T-cell Responses through Indirect Mechanisms and Restrains Tumor Growth

“…Results from mouse models demonstrate that the rescue of CD8 þ T-cell effector functions, such as Tbet-driven IFNg release, is key to success (17,41,42). In human cancer, we demonstrated that IFNg production can be recovered ex vivo selectively in Tbet hi tumor-infiltrating CD8 þ T cells (43). In line with previous findings in other mouse models (41), we found that Wnt3a neutralization exerted immunological effects mostly at the tumor site and not in the spleen, highlighting the relevance of tumor-infiltrating effector T-cell reactivation, rather than na€ ve or central memory T-cell expansion.…”

Function of Human Tumor-Infiltrating Lymphocytes in Early-Stage Non–Small Cell Lung Cancer

“…5D and F), suggesting additional factors might influence this heterogeneity. Expression of the transcription factor Eomes is associated with exhausted T cells (23)(24)(25)(26)(27)(28), and our intracellular flow cytometric assessment of Eomes revealed high expression in the CD8 þ TILs, with a significant negative correlation (r 2 ¼ 0.67, P < 0.0001) to IFNg production ( Fig. 6A).…”

Genetically driven CD39 expression shapes human tumor‐infiltrating CD8+ T‐cell functions

“…In addition, it described for the first time the role of a single nucleotide polymorphism modulating CD39 expression on CD8 + TILs, and supported the possibility that CD39 expression may represent a valid biomarker of partially exhausted CD8 + TILs, and even a novel immune checkpoint for restoring T-cell exhaustion. 26,27 Given the importance of CD8 + TILs in solid cancers and their impact on cancer survival, 28 and because the current checkpoint inhibitors (eg, ant-PD-1, anti-CTLA-4, anti-PDL-1 monoclonal antibodies [mAbs]) are not efficient for all tumor types or cause partial remission in the majority of tumors, [29][30][31][32] innovative immunotherapy strategies, particularly based on the combination of different approaches including new inhibitors providing immune check point blockade (ICB), [33][34][35] can strongly impact the phenotypic and functional features of CD8 + T cells in the TME.…”