Tumor-Derived Resistance

Mechanisms of Tumor-Derived Resistance in Immune Checkpoint Blockade Therapy

• Absence of antigenic proteins on the surface of tumor cells

The absence of antigenic proteins, such as viral antigens, tumor specific antigens, and tumor associated antigens, is the most direct indicator in defining restricted T cell recognition, which reduces tumor responses to immune checkpoint therapy. Tumor-targeted T lymphocytes reactivated by immune checkpoint blockade (ICB) have been observed to detect mutational tumoral neoantigens when treated with ICB. As a result, any tumor cell-related factor that can lead to a lack of cell surface antigens is likely to cause primary or acquired resistance to immune checkpoint therapy.

• Oncogenic signaling pathway mutations and modulations

Tumor cell resistance is inextricably linked to the cellular oncogenic signaling pathway. For example, researchers discovered that downregulated or altered components in the IFN- pathway (IFN-/JAK/STAT3) could aid tumor cells in evading IFN-'s killing effect, or directly decrease IFN-'s killing effect, contributing to tumor cell insensibility to T cells. MYC and STAT3 oncogenes could upregulate the expression of CD47 and PD-L1 by directly binding to their promoters, disrupting antitumor immunity. In the case of the tumor suppressor gene PTEN, either its inactivation or deletion would cause immunosuppression and interfere with the therapeutic effect of anti-PD-1 therapy, leading to ICB resistance.

• The presence of PD-L1

The immunosuppressive cell surface ligand PD-L1, which is constitutively produced by tumor cells, is an essential component of ICB therapeutic efficacy or resistance. The expression of PD-L1 on tumor cells allows them to "silence" activated T lymphocytes that detect tumoral neoantigens. Many signaling pathways and molecules have been discovered to be associated with PD-L1 expression, including EGFR mutations, MYC overexpression, PARP suppression, CDK5 problem, PDJ amplification, and PI3K/AKT mutations. Malignant tumors that express PD-L1 respond better to anti-PD-1 therapy. Recent evidence suggests that some PD-L1 variants released by tumor cells can act as "decoys" for PD-L1 targeted antibodies, inducing resistance to PD-L1 inhibition in NSCLC.

• Innate PD-1 resistance (IPRES)

Researchers discovered that PD-1 resistance is linked to a group of genes involved in mesenchymal transition (AXL, ROR2, WNT5A, LOXL2, TWIST2, TAGLN, and FAP), immunosuppression (IL10, VEGFA, and VEGFC), and monocyte and macrophage chemotaxis (CCL2, CCL7, CCL8, and CCL13) through their respective roles.

• Epigenetic alterations

Resistance to oncotherapy is usually associated with changes in gene expression, and aberrant epigenetic modification is a critical trigger of gene expression abnormality. Histone deacetylase inhibitors have been proven to boost MHC and tumor-associated antigen expression, increasing immune treatment's anti-tumor efficacy. So that histone deacetylation may play a significant function in the establishment and maintenance of ICB resistance. As tumoral DNA methylation was likely suppressed by hypomethylating drugs, CD80 expression was likely elevated in tumor cells, potentially leading to increased tumor infiltration of effector T cells.

• Absence of antigen presentation

MHC-I molecules that are necessary for antigen presentation include B2-microglobulin (B2M) and human leukocyte antigen (HLA). More specifically, loss of B2M expression reduces MHC class I cell surface expression, which in turn compromises antigen presentation to cytotoxic T cells leading to evading a cytotoxic T-cell antigen-specific immune response. A late-progressing lesion from a melanoma patient with an initial response to PD-1 treatment was revealed to have an acquired detrimental mutation in B2M.

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