NO. 62

CIMR Wednesday Lecture Series

Time:

Wednesday, Mar. 19 2025, 4:00 p.m.

Location:

Multi-function Hall, 2nd Floor, North Basic Research Building 

Host：

Yaping Huang (黄亚平)

Chinese Institutes for Medical Research, Beijing

Speaker：

Hanqiu Zheng (郑撼球)
School of Basic Medical Sciences
Tsinghua University

TITLE：

Dissecting the tumor-stromal interaction in metastasis and immune therapy resistance

ABSTRACT:

Tumor cells depend on the microenvironment for support, influencing metastasis, immune evasion, and therapy resistance. We have identified key mediators, including LTβ-LTβR and Jagged1-Notch in bone metastasis, and uncovered a metabolic interaction between osteoclasts and tumor cells that drives PARP inhibitor resistance. In our more recent work, our CRISPR-a sgRNA library screening, focused on signaling pathways, identified MALT1 as a dual-functional immune evasion gene. MALT1 promotes immune evasion through its paracaspase and death domain. In a paracaspase-dependent manner, MALT1 protects CD274 mRNA from degradation by its cleavage of ROQUIN1 and ROQUIN2. In a death-domain-dependent manner, MALT1 promotes the proliferation and polarization of tumor-associated macrophages to generate an immunosuppressive tumor microenvironment. Targeting MALT1 with antisense oligonucleotides inhibits PD-L1 expression in patient-derived tumor cells and suppresses the proliferation and M2-like polarization of tumor-associated macrophages isolated from patients with cancer. In preclinical models of solid tumors in female mice, treatment with MALT1 antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors. Together, our study demonstrates that targeting MALT1 is a potential strategy to overcome immune-checkpoint inhibitor resistance. These findings enhance our understanding of tumor-stroma interactions, highlighting promising therapeutic targets and potential synergistic treatment strategies for further exploration.

SELECTED PAPERS