Induction of Tertiary Lymphoid Structures With Antitumor Function by a Lymph Node-Derived Stromal Cell Line

Abstract

Tertiary lymphoid structures (TLSs) associate with better prognosis in certain cancer types, but their underlying formation and immunological benefit remain to be determined. We established a mouse model of TLSs to study their contribution to antitumor immunity. Because the stroma in lymph nodes (sLN) participates in architectural support, lymphogenesis, and lymphocyte recruitment, we hypothesized that TLSs can be created by sLN. We selected a sLN line with fibroblast morphology that expressed sLN surface markers and lymphoid chemokines. The subcutaneous injection of the sLN line successfully induced TLSs that attracted infiltration of host immune cell subsets. Injection of MC38 tumor lysate-pulsed dendritic cells activated TLS-residing lymphocytes to demonstrate specific cytotoxicity. The presence of TLSs suppressed MC38 tumor growth in vivo by improving antitumor activity of tumor-infiltrating lymphocytes with downregulated immune checkpoint proteins (PD-1 and Tim-3). Future engineering of sLN lines may allow for further enhancements of TLS functions and immune cell compositions.

The Crohn's-Like Lymphoid Reaction to Colorectal Cancer-Tertiary Lymphoid Structures With Immunologic and Potentially Therapeutic Relevance in Colorectal Cancer

“…Subcutaneous injections of the CRC cell line MC38 has also been used to study CLR (40, 57), although GCs were also not detected in this study (40). Unfortunately, neither of these models accurately reflects the pathogenesis and microenvironment of most human CRC.…”

“…Murine models have demonstrated a tumor-specific adaptive immune response (53, 54) that is driven by TLS even in the absence of secondary lymphoid structures (55). This host response can lead to tumor infiltration by immune cells and mediate tumor regression (54, 56, 57).…”

“…Induction and modification of TLS have been achieved in non-CRC human and murine studies, including in pancreatic cancer which is considered a non-immunogenic tumor (40, 53, 57, 59, 62). These exciting techniques, including tumor vaccines, Treg depletion, and cell line induced-TLS, have yet to be explored in CLR.…”

Tertiary lymphoid structures in the era of cancer immunotherapy

“…Other strategies have utilized stromal cells derived from lymph nodes to induce TLSs, exploiting their architectural support, lymphogenesis and lymphocyte recruitment properties (Box 2). The subcutaneous injection of a stromal cell line derived from lymph nodes induces TLSs that attract infiltration of host immune cell subsets and can improve the antitumour immune response against MC38 colon cancer xenografts in mice 129 . Several teams are also working on the development of synthetic scaffolds for cancer immunotherapy, aiming to induce immune responses locally, inside the tumour.…”

STING Signaling in Melanoma Cells Shapes Antigenicity and Can Promote Antitumor T-cell Activity

“…Lysis of melanoma cell targets by their HLA-matched TIL cultures was measured in a standard 5l Cr release assay, as described previously [22]. Briefly, 1 × 10 6 melanoma cells were labeled with 100 μCi of 51 Cr (Amersham Corp) for 2 h at 37°C.…”