Cancer arises from the proliferation of abnormal, uncontrolled cells that create dense masses, known as Solid Tumors. These cancer cells possess unique surface markers called antigens that can be identified by immune cells. A crucial component of our immune system, T cells, carry a protective protein known as FASL, which aids in destroying cancer cells. When T cells encounter cancer antigens, they become activated and initiate an attack on the tumor.
One form of immunotherapy, referred to as chimeric antigen receptor T cell therapy or CAR-T therapy, involves reprogramming a patient’s T cells to recognize cancer cell antigens. However, CAR-T therapy often struggles with solid tumors due to the dense, hostile environment within these tumors, which obstructs immune cells from infiltrating and functioning effectively.
Another significant hurdle that clinicians encounter when treating solid tumors is their heterogeneous composition of various cancer cell types. Some of these cells exhibit antigens recognizable by CAR-T cells, while others do not, complicating the design of CAR-T therapies that can target all tumor cells without harming healthy cells. Solid tumors also produce the protein Plasmin, which further impairs the immune system’s ability to break down FASL and eliminate cancer cells.
Researchers from the University of California, Davis investigated whether shielding FASL from plasmin could preserve its cancer-killing capabilities and enhance the efficacy of CAR-T therapy. They found that the human FASL protein contains a unique amino acid compared to other primates, making it more susceptible to degradation by plasmin. Their observations suggested that when FASL was cleaved, it lost its ability to kill tumor cells. However, after injecting an antibody that prevents plasmin from cleaving FASL, it remained intact and preserved its cancer-killing function.
Since directly studying cell behavior in the human body poses challenges, scientists culture tumor cells and cell lines in Petri dishes under controlled laboratory environments. To gain insights into plasmin’s role, the team examined ovarian cancer cell lines obtained from patients, discovering that CAR-T resistant cancer cells exhibited high plasmin activity.
They noted that combining ovarian cancer cells with elevated plasmin levels with normal cells displaying surface FASL diminished FASL levels in the normal cells. When they added FASL-protecting antibodies, CAR-T cells effectively eliminated not only the targeted cancer cells but also nearby cancer cells lacking the specific target antigen. These findings indicated that plasmin can cleave FASL in T cells and undermine CAR-T therapy, suggesting that safeguarding FASL may enhance CAR-T treatment’s effectiveness.
To assess whether tumor-generated plasmin can deactivate human FASL in more natural settings, researchers examined its function in live tumors within an active immune system. They implanted ovarian, mammary, and colorectal tumor cell lines from mice into genetically matched mice to elicit a natural immune response. When human FASL protein was directly injected into mouse tumors, the cancer cells remained intact. In contrast, injecting a drug that inhibits plasmin resulted in cancer cell death. Additionally, administering FASL-protecting antibodies also led to the elimination of cancer cells.
As a final experiment, the team aimed to determine whether activated T cells from the mice’s immune systems could penetrate the tumors and kill cancer cells. They implanted mice with both plasmin-positive and plasmin-negative tumors, treating both with drugs to enhance immune cell activity and boost FASL production.
They discovered that in tumors with low plasmin levels, mouse immune cells expressed high amounts of FASL on their surfaces, while in tumors with elevated plasmin levels, FASL was significantly reduced. Once again, injecting FASL-protected antibodies into these tumors increased FASL levels. The researchers concluded that plasmin can diminish the immune system’s ability to eliminate cancer cells by depleting FASL from immune cells.
In summary, the team found that tumors exploit plasmin to break down the protective protein FASL, evading immune system attacks. Based on their findings, they proposed that plasmin inhibitors or FASL-protected antibodies could augment the effectiveness of immunotherapy in treating cancer.
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Source: sciworthy.com
