Intratumoral antigen signaling traps CD8+ T cells to confine exhaustion to the tumor site.

Immunotherapy advances have been hindered by difficulties in tracking the behaviors of lymphocytes after antigen signaling. Here, we assessed the behavior of T cells active within tumors through the development of the antigen receptor signaling reporter (AgRSR) mouse, fate-mapping lymphocytes responding to antigens at specific times and locations. Contrary to reports describing the ready egress of T cells out of the tumor, we find that intratumoral antigen signaling traps CD8+ T cells in the tumor. These clonal populations expand and become increasingly exhausted over time. By contrast, antigen-signaled regulatory T cell (Treg) clonal populations readily recirculate out of the tumor. Consequently, intratumoral antigen signaling acts as a gatekeeper to compartmentalize CD8+ T cell responses, even within the same clonotype, thus enabling exhausted T cells to remain confined to a specific tumor tissue site.

Statins mediate anti- and pro-tumourigenic functions by remodelling the tumour microenvironment.

Anti-cancer properties of statins are controversial and possibly context dependent. Recent pathology/epidemiology studies of human lung adenocarcinoma showed reduced pro-tumourigenic macrophages associated with a shift to lower-grade tumours amongst statin users but, paradoxically, worse survival compared with that of non-users. To investigate the mechanisms involved, we have characterised mouse lung adenoma/adenocarcinoma models treated with atorvastatin. Here, we show that atorvastatin suppresses premalignant disease by inhibiting the recruitment of pro-tumourigenic macrophages to the tumour microenvironment, manifested in part by suppression of Rac-mediated CCR1 ligand secretion. However, prolonged atorvastatin treatment leads to drug resistance and progression of lung adenomas into invasive disease. Pathological progression is not driven by acquisition of additional driver mutations or immunoediting/evasion but is associated with stromal changes including the development of desmoplastic stroma containing Gr1+ myeloid cells and tertiary lymphoid structures. These findings show that any chemopreventive functions of atorvastatin in lung adenocarcinoma are overridden by stromal remodelling in the long term, thus providing mechanistic insight into the poor survival of lung adenocarcinoma patients with statin use.

Fibroblast-Derived STC-1 Modulates Tumor-Associated Macrophages and Lung Adenocarcinoma Development.

The tumor microenvironment (TME) consists of different cell types, including tumor-associated macrophages (TAMs) and tumor-associated fibroblasts (TAFs). How these cells interact and contribute to lung carcinogenesis remains elusive. Using G12DKRAS- and V600EBRAF-driven mouse lung models, we identify the pleiotropic glycoprotein stanniocalcin-1 (STC1) as a regulator of TAM-TAF interactions. STC1 is secreted by TAFs and suppresses TAM differentiation, at least in part, by sequestering the binding of GRP94, an autocrine macrophage-differentiation-inducing factor, to its cognate scavenger receptors. The accumulation of mature TAMs in the Stc1-deficient lung leads to enhanced secretion of TGF-ß1 and, thus, TAF accumulation in the TME. Consistent with the mouse data, in human lung adenocarcinoma, STC1 expression is restricted to myofibroblasts, and a significant increase of naive macrophages is detected in STC1-high compared with STC1-low cases. This work increases our understanding of lung adenocarcinoma development and suggests new approaches for therapeutic targeting of the TME.