Anti-cancer inhibitor could have dual effect

Anti-cancer inhibitor could have dual effect
Figure 1. Tissue transglutaminase (TG2) promotes peritoneal tumor growth in a syngeneic ovarian cancer (OC) mouse model by preventing CD8+ T cell infiltration into ascites. (A, B) Volume of peritoneal ascites (mean±SEM, n=23 per group, cumulative data from four independent experiments are shown) (A), and numbers of cells in ascites (mean±SEM, n=5 per group, data from one representative experiment out of two performed are shown) (B) in C57BL/6 (TG2+/+) and TG2 knockout (TG2-/-) female mice 6 weeks after intraperitoneal injection of ID8 cells. Shown are t-test p values. (C) Images of peritoneal metastases in TG2+/+ and TG2-/- abdominal cavities. Tumor implants are indicated by blue arrows. (D) Kaplan-Meier survival analysis of TG2+/+ (n=12) and TG2-/- (n=14) mice injected intraperitoneally with ID8 cells. Graph represents data from one experiment out of two performed. (E–H) Measurements by flow cytometry of percentages of immune cells in TG2+/+ and TG2-/- mice-bearing tumors induced by intraperitoneal inoculation of ID8 cells. (E) CD8+ and CD4+ T cells in spleens (TG2+/+, n=10; TG2-/-, n=9; data from two experiments). (F) CD8+ and CD4+ T cells in abdominal ascites (TG2+/+, n=13; TG2-/-, n=16; data from four experiments). (E, F) Programmed cell death protein 1 (PD-1) expressing CD8+ T cells in spleen (n=7 per group; data from one representative experiment) and ascites (n=9 per group; data pooled from three experiments). Values are means ± SEM (*p<0.05; **p<0.01). (G, H) T regulatory cells (Tregs) in spleen (n=10 per group; data from two experiments) and ascites (n=13 per group; data from three experiments). Activation marker expressions from one representative experiment are shown (n=4–7 per group). (I) Absolute cell counts in ascites (TG2+/+, n=6; TG2-/-, n=5). Total cell counts were used for determination of total cell number for each subset from data retrieved from fluorescence activated cell sorting (FACS, ****p<0.0001). Credit: DOI: 10.1136/jitc-2021-002682

TG2, an enzyme known to help cancers spread more quickly, also plays a role in regulating T-cells, according to a Northwestern Medicine study published in the Journal for ImmunoTherapy of Cancer.

Inhibiting TG2 in non-cancer cells also boosted immune activity, a phenomenon that could be leveraged in , according to Daniela Matei, MD, the Diana, Princess of Wales Professor of Cancer Research, chief of Reproductive Science in Medicine in the Department of Obstetrics and Gynecology and senior author of the study.

"If we create a drug that inhibits TG2, it could work in cancer cells and in host cells," said Matei, who is also a professor of Medicine in the Division of Hematology and Oncology.

Matei's laboratory has studied the impact of elevated TG2 expression in ovarian cancer for a decade, consistently finding that TG2 increases ovarian cancer's spread to other locations in the body. However, what impact TG2 has in remained unknown.

In the current study, Matei and co-author Bin Zhang, MD, Ph.D., professor of Medicine in the Division of Hematology and Oncology and of Microbiology-Immunology, studied the effects of knocking out expression of the gene that codes for TG2 in mouse models of .

The investigators discovered that, surprisingly, loss of TG2 in healthy cells is accompanied by a more robust immune response. Without TG2, an imbalance in STAT proteins causes increased cytotoxic T-cell activity, leading to reduced tumor progression.

"TG2 is necessary in the body, so we believe loss of TG2 triggers this compensatory mechanism," Matei said.

Matei and collaborators are currently exploring strategies to inhibit TG2 in cancer cells, but now are designing inhibitors that will work in immune cells as well.

"Our current inhibitor is designed to block adhesion of cancer cells to the , but other approaches can degrade the entire TG2 protein—which could help kill , alter anti-tumor immunity and delay cancer progression," Matei said.

More information: Livia Elena Sima et al, Loss of host tissue transglutaminase boosts antitumor T cell immunity by altering STAT1/STAT3 phosphorylation in ovarian cancer, Journal for ImmunoTherapy of Cancer (2021). DOI: 10.1136/jitc-2021-002682

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