Context-Dependent Effects Explain Divergent Prognostic Roles of Tregs in Cancer

SIMPLE SUMMARY: Immune cells play an important role in cancer, with regard to classification, diagnostic or prognostic matters. In particular, we focused on the prognostic value of Tregs in this meta-analysis. We took into account the local context and their heterogeneity in order to solve their apparent ambiguous role. We used three proxies to recapitulate the complexity of the context: the neighboring cell, the tissue and the quantification method; and we carefully dissected the regulatory population into existing subsets. We showed that CD45RO [Formula: see text] Tregs had a reproducible negative prognostic value across all five cancer types studied (breast, colorectal, gastric, lung and ovarian). It suggests that Tregs from an homogeneous context have a consistent prognostic role across cancer types. ABSTRACT: Assessing cancer prognosis is a challenging task, given the heterogeneity of the disease. Multiple features (clinical, environmental, genetic) have been used for such assessments. The tumor immune microenvironment (TIME) is a key feature, and describing the impact of its many components on cancer prognosis is an active field of research. The complexity of the tumor microenvironment context makes it difficult to use the TIME to assess prognosis, as demonstrated by the example of regulatory T cells (Tregs). The effect of Tregs on prognosis is ambiguous, with different studies considering them to be negative, positive or neutral. We focused on five different cancer types (breast, colorectal, gastric, lung and ovarian). We clarified the definition of Tregs and their utility for assessing cancer prognosis by taking the context into account via the following parameters: the Treg subset, the anatomical location of these cells, and the neighboring cells. With a meta-analysis on these three parameters, we were able to clarify the prognostic role of Tregs. We found that CD45RO [Formula: see text] Tregs had a reproducible negative effect on prognosis across cancer types, and we gained insight into the contributions of the anatomical location of Tregs and of their neighboring cells on their prognostic value. Our results suggest that Tregs play a similar prognostic role in all cancer types. We also establish guidelines for improving the design of future studies addressing the pathophysiological role of Tregs in cancer.