FGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells

Abstract

Although tissue-resident memory T (TRM) cells specific for previously encountered pathogens have been characterized, the induction and recruitment of brain TRM cells following immune therapy has not been observed in the context of glioblastoma. Here, we show that T cells expressing fibrinogen-like 2 (FGL2)–specific single-chain variable fragments (T-αFGL2) can induce tumor-specific CD8+ TRM cells that prevent glioblastoma recurrence. These CD8+ TRM cells display a highly expanded T cell receptor repertoire distinct from that found in peripheral tissue. When adoptively transferred to the brains of either immunocompetent or T cell-deficient naïve mice, these CD8+ TRM cells reject glioma cells. Mechanistically, T-αFGL2 cell treatment increased the number of CD69+CD8+ brain-resident memory T cells in tumor-bearing mice via a CXCL9/10 and CXCR3 chemokine axis. These findings suggest that tumor-specific brain-resident CD8+ TRM cells may have promising implications for the prevention of brain tumor recurrence.

CD8+ T cell-derived Fgl2 regulates immunity in a cell-autonomous manner via ligation of FcγRIIB

“…In vivo and in vitro, in mice and human T cells, we more definitively show that binding of FcγRIIB by Fgl2 elicits apoptosis of FcγRIIB + CD8 + T cells, forming a negative regulatory loop governing antigen-specific CD8 + T cells. Our studies are corroborated by a recent report which showed that blocking Fgl2 in glioma results in a preservation of FcγRIIB + CD8 + T cells in mice 44 . Together, these data bring to light a potential mechanism by which exhausted CD8 + T cells actively dampen the T cell response via physical deletion of FcγRIIB + CD8 + T cells.…”

“…This work extends the work of other groups that have shown that Fgl2 has a protumor role in the context of glioma and hepatocellular carcinoma 29 , 30 , 40 , 44 – 46 . However, previous studies have focused on the impact of Fgl2 produced from regulatory T cells, macrophages and tumor-associated cells (stroma, fibroblasts) as these cell types are known cellular sources of Fgl2 that can mediate immunosuppression on T cells 28 – 30 , 32 , 33 , 40 – 42 , 45 – 49 .…”

“…However, as Fgl2 is not just an immunosuppressive cytokine, but a prothrombinase, the broad-scale manipulation of Fgl2 (e.g. Fgl2 blocking antibody described by others 44 , 50 ) may have detrimental systemic effects as Fgl2 aids in coagulation, wound healing, and tolerance. These data build a compelling case that manipulation of Fgl2 from CD8 + T cells either via TIL or CAR-T cell therapy could prolong the function and persistence of these cells without the systemic side effects of blocking Fgl2 from all cellular sources.…”

Persistent tailoring of MSC activation through genetic priming

“…Both priming methods induced transcriptional changes, yielding over 1900 differentially expressed genes (DEGs), each relative to untreated control MSCs (p < 0.05; FC > 2) (Figure 2A-C). In addition to IDO1 , upregulated DEGs included COX-2 ( PTGS2 ), a second key immunomodulatory effector enzyme that produces the anti-inflammatory small molecule prostaglandin E2 42 (PGE2), along with multiple effector genes associated with T cell suppression including IL4I1 , 43 Galactin-9 44,45 (LGALS9) , PD-L2 46 ( PDCD1LG2 ), and FGL2 47 (Figure 2A). Along these lines, normalized enrichment scores from gene ontology (GO) analysis show transcription in both MSC IRF1 and MSC IFNγ is positively enriched for genes corresponding to the GO terms ‘negative regulation of T cell proliferation’ (0042130) and ‘negative regulation of T cell activation’ (005086800) (Figure 2D, Supplemental Figure S5).…”

Aspirin and immunotherapy: a Faustian bargain?

“…During viral infection, FGL2 –/– mice possess a higher frequency of DCs expressing CD80, CD86, and MHC; they also show decreased PD-1 expression on T cells and increased B and T cell effector responses ( 11 ). We have shown through a series of studies of preclinical glioma that FGL2 increases the expression of PD-1 and the frequency of tumor-supportive macrophages and Tregs, suppresses the development of CD103 + DCs, and blocks the recruitment of tumor-specific, brain-resident memory T cells ( 7 , 12 , 13 ). In other cancers, FGL2 expression was associated with better prognostic outcomes and increased lung cancer infiltration of immune cells, such as CD8 + T cells, macrophages, B cells, and DCs ( 14 ).…”