Innate (Primary) and Acquired (Secondary) Resistance

Introduction of Innate (Primary) and Acquired (Secondary) Resistance

Resistance to immune checkpoint blockade (ICB) therapy can be initially divided into two types: innate (primary) resistance and acquired (secondary) resistance. Innate resistance refers to the initial lack of response to ICB therapy, even before treatment initiation. Acquired resistance is resistance that develops during or after ICB therapy. Tumors that respond to treatment initially may develop resistance.

Ongoing research suggests that tumor cell-intrinsic and tumor cell-extrinsic components both contribute to resistance mechanisms. The most obvious reason for a tumor's failure to respond to ICB treatment is a lack of detection by T cells due to the absence of tumor antigens. Cancer cells, on the other hand, may have tumor antigens but evolve ways to avoid displaying them on the surface restricted by MHC, either by alterations in the antigen presentation apparatus or through mutations in the antigen presenting machinery.

Mechanisms of Innate and Acquired Resistance in ICB Therapy

• Tumor Cell-Intrinsic Factors

Tumor cell-intrinsic factors that lead to immunotherapy resistance include tumor cell proliferation or regulation of specific genes, as well as pathways that inhibit immune cells from infiltrating or functioning within the tumor microenvironment.

1) MAPK pathway or loss of PTEN expression

Oncogenic signaling via the MAPK pathway results in the production of VEGF and IL-8, among many other secreted proteins that have been demonstrated to impair T cell recruitment and function. By enhancing PI3K signaling, PTEN deficiency is associated with ICB resistance.

2) Expression of WNT/β-catenin signaling pathway

Human melanoma tumors that were not inflamed by T cells or CD103⁺ DCs in the tumor microenvironment showed considerably higher expression of tumor intrinsic β-catenin signaling genes.

3) Loss of IFNγ signaling pathways

An analysis of tumors from patients who did not react to anti-CTLA-4 antibody therapy found an increased prevalence of mutations in the IFNγ pathway genes IFNγ receptor 1 and 2, JAK2, and IRF1. Any of these variations would impair IFNγ signaling and provide tumor cells an advantage in evading T cells, leading to primary resistance to anti-CTLA-4 therapy.

4) Lack of T cell responses due to loss of tumor antigen expression.

Mutations in immunological-related gene expression caused by epigenetic DNA mutations within cancer cells can impact antigen processing, presentation, and immune evasion.

Fig 1 Intrinsic mechanisms of resistance to immunotherapy.¹

• Tumor Cell-Extrinsic Factors

1) Regulatory T cells (Tregs)

It is discovered that Tregs suppress effector T cell (Teff) activity via the secretion of inhibitory cytokines such as IL-10, IL-35, and TGF-β, as well as direct cell contact. Response to anti-CTLA-4 therapy in mouse models suggests that immunotherapy is unable to increase Teff or deplete Tregs and can produce treatment resistance, either initially or during recurrent disease.

2) Myeloid derived suppressor cells (MDSCs)

According to studies, the presence of MDSCs in the tumor microenvironment correlates with decreased immunotherapy efficacy, including immune checkpoint therapy, adoptive T cell therapy, and DC vaccination.

3) Macrophages

According to reports, macrophages in hepatocellular carcinoma and B7-H4 in ovarian cancer can directly decrease T cell responses via PD-L1.

4) Other inhibitory immune checkpoints

Enhanced production of IFN by effector T cells promotes the development of the PD-L1 protein on a variety of cell types, which may recognize the PD-1 receptor on T cells, reducing anti-tumor immunity. TIM-3 expression on T cells was also found to be increased in two lung cancer patients who developed recurrent disease following anti-PD-1 treatment.

Fig 2 Extrinsic mechanisms of resistance to immunotherapy.¹

Based on in-depth research on the mechanisms of resistance to primary and acquired in ICB therapy, Creative Biolabs provides you with professional immune checkpoint-related services. Please contact us if you require any other information.

Reference

1. Sharma, Padmanee et al. "Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy." Cell vol. 168,4 (2017): 707-723.

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