Scientists Develop Methods to Overcome Immunotherapy Resistance in Cancer Patients

Scientists in China and Australia have independently identified methods to improve the effectiveness of cancer-fighting T cells within tumors, potentially addressing why up to 60% of patients fail to respond to immune checkpoint blockade therapy. Immune checkpoint blockade has revolutionized the treatment of cancers like melanoma, but the reasons behind lack of response remain unclear.

Chinese scientists have established a new technology platform called CLIM-TIME (CRISPR-Laser-captured microdissection Integration Mapping of Tumor Immune Microenvironment) that reveals how genetic mutations in tumors reshape the microenvironment and modulate immune responses. The study, published in the journal Cell on Thursday, was jointly conducted by a Shanghai-based team from the Center for Excellence in Molecular Cell Science at the Chinese Academy of Sciences, in collaboration with teams from Shanghai Jiao Tong University, and Guangzhou Laboratory.

Using the new technology platform, the researchers analyzed 391 common tumor suppressor genes to see how they reshape the tumor microenvironment and classified them into seven distinct subtypes. The researchers found that the loss of certain tumor suppressor genes triggers a massive buildup of collagen. This excess collagen makes the tumor structure so dense that it acts like a wall, preventing T cells from reaching and killing the cancer.

The team identified a specific molecule called LOXL2 as the architect of this barrier. In tests on mice, researchers found that by blocking LOXL2, they could dissolve the collagen wall. This allowed T cells to penetrate the tumor and significantly boosted the power of immunotherapy drugs.

One major issue with CAR-T cell therapy is that it can't enter solid tumors. When treating human tumors with CAR-T, if a small molecule is used to target this protein, it could significantly improve CAR-T treatment outcomes, though clinical application still requires safety evaluation. CAR-T is an immunotherapy involving the genetic engineering of a patient's T-cells to recognize and attack cancer cells.

In separate research, Australian scientists led by professors from Peter Mac and the University of Western Australia have identified a new way to enhance the quality and durability of anti-tumor T cell responses. Results of this research have been published in the journal Nature Immunology.

The process involves a protein called Fms-related tyrosine kinase 3 ligand (Flt3L) which occurs naturally in the body and which is required for healthy functioning of dendritic cells—key immune cells which instruct T cells how and when to respond. The researchers demonstrated that increasing Flt3L levels expanded specialized dendritic cells in the lymph node closest to the tumor—where the immune response starts—which in turn primed a population of early-phase T cells capable of sustaining anti-tumor responses.

An enhanced tumor killing effect was observed in mice treated with lab-generated Flt3L and an ICB drug (anti-CTLA-4 therapy). One of the ways cancer hides from the immune system is by silencing T cells, and ICB works by blocking receptors on these T cells so the cancer can no longer switch them off. The research has identified a new way to ensure better-quality, long-lived T cells are generated and maintained so that when they reach the tumor tissue, ICB can keep them engaged in the fight against cancer.