Cell research: Individualized medicine in anti-tumor immunotherapy

The blocking antibody ipilimumab of Cytotoxic T lymphocyte antigen-4 (CTLA-4) is able to elicit an immune response in a subset of melanoma patients to achieve consistent tumor growth. However, as a kind of effective immunization-inducing drug, there is currently no clinical biomarker indicating the therapeutic effect of this drug. Recently, the Laurence Zitvogel team of the Gustave-Roussy Cancer Institute in France published their online research on molecular markers in ipilimumab immunotherapy in Cell Research.

CTLA-4 is a kind of negative regulatory molecule on the surface of T cells. After blocking the signal of CTLA-4, theoretically, the negative regulation signal of T cells will be greatly attenuated, and the immune effect will be enhanced. When T cells are activated, they express a large number of effector cytokines such as IL-2, IFN-γ and the like.

First, the authors examined the effects of IL-2R on the treatment of ipilimumab. The results showed that when antibodies were used to block IL-2, IL-15 (both bind to IL-2Rβγ receptor), or directly block the receptors IL-2Rα and IL-2Rβ, the effect of ipilimumab on immunotherapy was It was suppressed. Later, the authors found that when using soluble CD122 (a class of proteins that compete with IL-2 for binding to IL-2Rβ) in combination with ipilimumab, the anti-tumor physiological indicators of cancer-bearing mice (including the ratio of effector T cells, IFN-γ) Secretion concentration, tumor volume, etc.) all decreased significantly. The above results indicate that the loss of IL-2R inhibits the enhancement of the immune response by the treatment of ipilimumab.

Later, the authors found that IL-2 can enhance the anticancer effect of ipilimumab by artificial injection of recombinant IL-2. Further studies have found that under physiological conditions, the inhibition of CTLA-4 by ipilimumab can indirectly promote the release of IL-2, and at the same time, the tumor site will be enriched with a large number of CD4+Lag3+ effector T cells. The authors believe that IL-2 may be released by this part of CD4+Lag3+ T cells. The expression levels of IL-2 in CD4+Lag3+ T cells and other subpopulation T cells after stimulation with CTLA-4 were compared. The results showed that the expression of IL-2 in CD4+Lag3+ T cells was much higher than that in other groups, and the expression of FoxP3 was down-regulated. The above results indicate that CD4+Lag3+ T cells are the main effector T cells after ipilimumab treatment.

CD25 is another class of molecules that bind to IL-2R to inhibit IL-2 signaling. The authors found that patients with metastatic melanoma had significantly elevated levels of CD25 expression in serum after receiving ipilimumab and rIL-2. The authors artificially injected sCD25 into model mice, and the results showed that artificial increase in sCD25 resulted in an increase in Treg in mice. Other evidence also suggests that CD25 inhibits the immune activation effect caused by ipilimumab.

Finally, the authors analyzed the association of sCD25 levels with their longevity in patients. The results showed that patients with high levels of sCD25 had shorter lifespan than patients with lower levels. Therefore, they believe that sCD25 can be used as a type of ipilimumab-targeted biomarker to determine whether ipilimumab is effective in treating a patient.