Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Immunotherapy, including T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs), aims to eliminate cancer cells via cytotoxic T lymphocytes.
• Efficient delivery and engagement of T cells are critical, with the assumption that tumor elimination is guaranteed if inhibitory factors are managed.

Purpose of the Study:

• To investigate the mechanisms by which cancer cells develop resistance to T cell-mediated killing, particularly in the context of HER2-targeted immunotherapies.
• To identify specific molecular pathways involved in conferring resistance to T cell-mediated cytotoxicity.

Main Methods:

• Utilized TCBs and CARs engineered to target HER2-expressing cancer cells.
• Developed and analyzed multiple independently generated models of T cell-mediated killing resistance.
• Investigated the role of interferon-gamma signaling and its downstream components, including JAK2, in resistance.

Main Results:

• Disruption of interferon-gamma signaling was identified as a key mechanism conferring resistance to killing by T lymphocytes.
• The Janus kinase 2 (JAK2), a critical component in the interferon-gamma signaling pathway, was found to be repeatedly disrupted in resistant cancer models.
• These findings suggest a common resistance strategy employed by cancer cells against redirected T cells.

Conclusions:

• Interferon-gamma signaling is essential for effective T cell-mediated cancer cell killing.
• Cancer cells can evade immunotherapy by disrupting the JAK2-mediated interferon-gamma pathway.
• Long-term inhibition of this pathway might impair tumor immunoediting and potentially promote tumor progression, highlighting a critical vulnerability in cancer immunotherapy.