Interferon-γ Pathway Helps Cancer Cells Evade Immune Therapy

Immunotherapy is one of the most potent therapies being developed against cancer. Recruiting the patient’s own immune system to infiltrate the tumor and specifically attack cancer cells has high rates of success in blood cancers compared to other therapeutic interventions. However, it does not work effectively in solid tumors. This has led to research into ineffective infiltration of T-cells, tumor microenvironment, immune suppression, and immune checkpoint regulation.

 

CAR T-Cell Therapy

Increasing the immunogenicity of a tumor is a valid strategy to safely eliminate cancer cells without damaging normal cells. In a bid to improve immune targeting of tumor cells, CAR-T cell therapy was developed. Challenging the patient’s T cells with a synthetic antigen that contains a part of an antigenic protein from the patient’s tumor can help engineer chimeric antigen receptors (CARs) on T-cells. T-cells with these special receptors can home into the tumor cell based on the antigen and mount a robust elimination response.

 

T-Cell Bispecific Antibodies

A variant of CARs is T-cell bispecific antibodies (TCBs) which combine the cancer-specific antigen with a T-cell effector recruiting antigen. This allows both tumor homing and recruitment of other immune cells like NK cells or effector T cells to maximize immune response.

 

Results

In a recent report in Nature Communications, scientists from Vall D’Hebron Institute of Technology, Barcelona, discover a new mechanism by which tumor cells can evade immune attack by cytotoxic T lymphocytes in a breast cancer model. HER2 is a tyrosine kinase that is overexpressed in breast cancer. The authors developed CARs and TCB targeting HER2 and studied the immune response, or lack thereof, in HER2-driven cancer cell lines and patient xenografts. Interestingly, they found that in response to CAR and TCB therapies, tumor cells show defects in IFN-gamma signaling which provides resistance to immune therapy and aids tumor progression. 

Interferongamma (IFN‐γ), a cytokine, “acts as an interrupter that controls cell death. Certain cancer cells learn to switch off this pathway and thus survive the attack of lymphocytes.” According to co-First Author Enrique J. Arenas “at present, there is no easy way of applying this discovery in clinical practice. Namely, to effectively identify those patients who have this pathway turned off.” This represents the next step in this research; “to develop a simple method to be able to do so,”

This study unravels an important facet of tumor immune resistance. JAK2 inhibitors are widely used in cancer therapy to treat several cancers.  JAK2 is one of the components of the IFN‐γ pathway. Results from this study show that downregulation of JAK2 may help tumor progression and develop immune resistance, indicating that we need to consider several aspects of the tumor microenvironment while developing effective therapies.

The director of the study, Joaquín Arribas, hopes to launch clinical trials in the future to develop better CAR-T therapies in breast cancer. “Driven by our discoveries, we aim to more precisely screen patients for enrollment in this clinical study, better predict when resistance will occur and develop strategies to overcome the mechanisms that govern this resistance,” he said.

Related Article: AbbVie Signs Off-the-Shelf CAR-T Therapy Pact with Jennifer Doudna’s Caribou Biosciences

References

  1. https://www.nature.com/articles/s41467-021-21445-4
  2. https://www.vhio.net/vhio-led-study-unveils-novel-mechanism-of-resistance-to-t-cell-bispecific-antibodies-and-car-t-targeting-her2-breast-cancer/

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