Nat Commun: The mechanism of cancer cell resistance to immunotherapy

Nat Commun: The mechanism of cancer cell resistance to immunotherapy. Nature Communication: Research reveals the mechanism by which cancer cells develop resistance to immunotherapy. 

Immunotherapy continues to show exciting promise in combating specific tumor types. Many current strategies focus on ensuring that active toxic T cells are delivered directly to the vicinity of tumor cells. It is believed that as long as the immunosuppressive mechanism of cancer cells is blocked, once lymphocytes bind to cancer cells, they will be destroyed.

The results of a study published in the journal Nature Communications revealed how cancer cells escape the killing of lymphocytes through the interference of interferon-γ signaling. Enrique J. Arenas and Alex Martínez-Sabadell, postdoctoral researchers in the growth factor research group of Joaquín Arribas of VHIO, are co-authors of the study.

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“Although these immune-based methods have been approved for the treatment of certain hematological malignancies, they have failed to show efficacy in clinical studies of solid tumors. This failure was previously related to the inability of T cells to directly target cancer cells successfully. So far, there have been few reports on the mechanisms used by tumors to make them resist T cell attack. This has always been the focus of our current research.” said Joaquín Arribas, director of the Joint Program for Preclinical and Translational Research.

“Cancer researchers are currently adopting several different strategies to overcome these resistance mechanisms. Our goal is to take a step forward by determining whether there are more mechanisms for cancer cells to overcome the attack of targeted lymphocytes.”

By using HER2-driven cell lines and PDX, as well as TCB and CAR that target HER2, researchers have now revealed a new mechanism that is resistant to redirected T cells. Specifically, they found that even if active cytotoxic cells were successfully delivered to tumor cells, the latter also adopted strategies to avoid being cleared by lymphocytes. The results of the study indicate that the destruction of interferon-gamma signals confers resistance and thus promotes disease progression.

Interferon-γ (IFN-γ) is a cytokine that plays an important role in inducing and regulating a series of immune responses. “It acts as a blocker to control cell death. Some cancer cells learn to shut down this pathway and survive lymphocyte attack. At present, there is no easy way to apply this discovery to the clinic in practice. That is, how effective To identify those patients whose pathways are closed. This is also the next step in our research.”

A previous study led by Joaquín Arribas was published in “Science Translational Medicine”, showing that the p95HER2-T cell bispecific antibody can successfully guide lymphocytes directly to cancer cells for targeted killing. This novel immunotherapy method can be used For the treatment of certain HER2 + breast cancers. This direct delivery is achieved due to the p95HER2 protein located only in tumor cells. For patients who have stopped responding to current therapies, this represents a new treatment approach and new hope.

Joaquín Arribas concluded: “Based on our findings, our goal is to screen patients for this clinical study more accurately, to better predict when resistance will appear, and to develop strategies to overcome and control this resistance. Mechanisms.”

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