Antitumor Immune Responses in B2M-Deficient Cancers.

Area of Science:

• Immunology
• Oncology
• Cancer Immunology

Background:

• Beta-2 microglobulin (B2M) is essential for MHC class I presentation of tumor antigens.
• Loss of B2M confers resistance to immune checkpoint blockade (ICB) therapies.
• Tumors with B2M inactivation have shown response to ICB, necessitating investigation into alternative immune response mechanisms.

Purpose of the Study:

• To investigate immune responses in B2M-inactivated tumors treated with anti-PD-1 therapy.
• To explore mechanisms of anti-tumor immunity in the absence of surface MHC class I.
• To analyze the role of B2M alterations in human melanoma response to PD-1 blockade.

Main Methods:

• B2M knockout in three murine cancer models with varying MHC class I expression and anti-PD-1 sensitivity.
• Analysis of immune cell populations (CD4+ T cells, NK cells) mediating anti-tumor responses.
• Examination of pretreatment melanoma biopsies (n≈300) for B2M mutations, LOH, and copy-number variations.

Main Results:

• B2M-deficient MC38 and YUMMER2.1 models responded to anti-PD-1 and IL2 agonist, mediated by CD4+ T cells and NK cells.
• Aggressive B16 model with B2M deficiency showed partial response to IL2 agonist, dependent on NK cells.
• In human melanoma, B2M loss of heterozygosity (LOH) was enriched in non-responders and associated with increased activated NK cell infiltration.

Conclusions:

• CD4+ T cell and NK cell activation can mediate responses to PD-1 blockade in B2M-deficient murine models.
• Activated NK cells in human melanoma with partial B2M loss may prevent tumor escape via reduced MHC class I expression.