ILT2 and ILT4 Drive Myeloid Suppression via Both Overlapping and Distinct Mechanisms

Area of Science:

• Immunology
• Oncology
• Cancer Biology

Background:

• Solid tumors create a complex microenvironment that suppresses anti-tumor immune responses.
• Immunoglobulin-like transcript (ILT)2 and ILT4 are immune-suppressive receptors implicated in myeloid cell inhibition within tumors.
• The specific roles of ILT2 and ILT4 in solid tumor immune suppression require further elucidation.

Purpose of the Study:

• To investigate the distinct and combined contributions of ILT2 and ILT4 to myeloid cell inhibition in solid tumors.
• To evaluate the therapeutic potential of dual ILT2/ILT4 blockade in reprogramming the tumor microenvironment.

Main Methods:

• Utilized a 3D spheroid tumor model to assess myeloid cell activation.
• Employed humanized mouse tumor models to study in vivo immune responses.
• Analyzed human tumor explant histoculture systems to validate findings.

Main Results:

• ILT2 inhibits myeloid cells via MHC-I trans-engagement, while ILT4 inhibits via cis- or trans-engagement.
• Combined ILT2/ILT4 blockade optimally activated myeloid cells, increasing CXCL9/CCL5 secretion and CD86 expression, while decreasing CD163.
• Dual blockade in humanized mice and tumor explants enhanced immune activation, cytolytic T-cell activity, and M1 macrophage polarization.

Conclusions:

• ILT2 and ILT4 have distinct mechanisms for suppressing myeloid cells in the tumor microenvironment.
• Combined blockade of ILT2 and ILT4 is a promising strategy for reprogramming myeloid cells.
• This approach holds potential for enhancing anti-tumor immunity and improving clinical responses to cancer immunotherapies.