CTLA-4 promotes lymphoma progression through tumor stem cell enrichment and immunosuppression

Abstract

The recurrence rate of lymphoma is very high, and tumor stem cells may be an important mechanism. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) can inhibit antitumor immunity and promote cancer progression, but its role and mechanism in lymphoma are still unclear. Here we collected lymphoma tissue and peripheral blood from patients with diffuse large B-cell lymphoma (DLBCL). Results showed that CTLA-4 expression and CD44+ cell in the high-risk group were significantly higher than that in the low-risk group. Correlation analysis showed that CTLA-4 expression positively correlated with CD44+ cell in lymphoma tissue and regulatory T (Treg) cells in lymphocytes. In vitro experiment showed that CTLA-4 increased the ratio of lymphoma stem cells, and proliferation and invasion of lymphoma cells through TGF-β pathway. Moreover, CTLA-4 enhanced the proliferation of Treg cells induced by lymphoma cells. Animal experiments showed that CTLA-4 can promote transplanted lymphoma growth. Immunohistochemistry results showed that both Ki-67 and CD44+ cells increased significantly in the CTLA-4 group. TGF-β neutralization can significantly block these effects of CTLA-4. In conclusion, CTLA-4 promoted DLBCL progression through lymphoma stem cell enrichment and immunosuppression.

Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: implications for novel therapeutic strategies

“…Emerging research suggests that CSCs employ immune evasion through the upregulation of immune checkpoint ligands [ 122 – 125 ]. In various types of cancer, including gastric, breast, malignant mesothelioma, bladder, lung, melanoma, and pancreatic cancers, PD-L1 expression is associated with CSC marker expression, tumor growth, and aggressiveness [ 124 ].…”

“…Moreover, the expression of Cytotoxic T Lymphocyte antigen 4 (CTLA-4) is higher on CSCs compared to normal cancer cells [ 126 ]. CTLA-4 acts as an analog of CD28 and suppresses T cell activation by blocking co-stimulation [ 125 ]. In the context of lymphoma, elevated CTLA-4 expression is linked to an increased proportion of lymphoma stem cells and enhanced proliferation and invasion of lymphoma cells via the TGF-β pathway [ 125 ].…”

“…CTLA-4 acts as an analog of CD28 and suppresses T cell activation by blocking co-stimulation [ 125 ]. In the context of lymphoma, elevated CTLA-4 expression is linked to an increased proportion of lymphoma stem cells and enhanced proliferation and invasion of lymphoma cells via the TGF-β pathway [ 125 ]. Furthermore, CTLA-4 on CSCs promotes the proliferation of regulatory T cells, which primarily serve to inhibit T cell function [ 125 ].…”

“…In the context of lymphoma, elevated CTLA-4 expression is linked to an increased proportion of lymphoma stem cells and enhanced proliferation and invasion of lymphoma cells via the TGF-β pathway [ 125 ]. Furthermore, CTLA-4 on CSCs promotes the proliferation of regulatory T cells, which primarily serve to inhibit T cell function [ 125 ]. Additionally, the transmembrane protein CD47 plays a crucial role in immune evasion for CSCs [ 127 ].…”

Targeting CD47-SIRPα axis for Hodgkin and non-Hodgkin lymphoma immunotherapy

“…High expression of programmed death-ligand 1 and 2 (PD-L1/2) in malignant lymphoma causes T-cell dysfunction, exhaustion, and subsequent apoptosis through the PD-1/PD-L1 signaling pathway. 13 Other inhibitory ligands, such as B- and T-lymphocyte-associated protein (BTLA), 14 , 15 cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), 16 and CD160 17 are also active in the tumor microenvironment of lymphoma and suppress immune cell function. In addition, myeloid-derived suppressor cells and immature monocytic myeloid cells promote regulatory T (Treg) cell differentiation and suppress effector T-cells in B-cells lymphoma 18 ( Fig.…”