T Cell-Based Resistance

T cells are lymphocytes that play critical roles in the immune response to cancer because they can recognize pieces of specific antigens on tumor cells that are presented by DCs with their MHC. T cells work primarily through the activation of T cell receptors and downstream signaling pathways, allowing cancer cells to be detected and killed, preventing the creation of solid tumors.

Mechanisms of T Cell-Based Resistance in ICB Therapy

• T cell deficiency

T cells are the executors at the frontline of cancer's innate defense, and their lethal effect is critical in immunological checkpoint blockade (ICB) therapy. Immunotherapy inefficiency is caused by a lack of tumor-specific T cells or a loss of T cell activity, resulting in nonresponsiveness/resistance to ICBs. It is worth noting that a paucity of T cells in the regional tumor microenvironment (TME) can be attributed to failed tumor infiltration and aberrant distribution of functional T cells. As an example, the β-catenin signaling pathway is more intensively active in tumors and T cells in human melanoma, whereas CD103⁺ DCs are uncommon in TME. Similar findings suggest that the β-catenin signaling pathway reduces CD8⁺ T cell invasion in colorectal cancer and, ultimately, T cell exclusion in TME.

• Other suppressive immune checkpoint molecules

In addition to the most widely targeted immune checkpoints, CTLA-4 and PD-1, additional checkpoints such as TIM3, LAG3, TIGIT, B7-H3, CD38, CD73, and A2A receptors are being studied. PD1, which interacts with PDL1, is largely expressed after T cell activation and inhibits T cell effector activity, causing T cells to enter a gradual dysfunctional condition known as exhaustion. Among exhausted T cells, anti-PD1/PDL1 mAbs are likely to reactivate PD-1^low CXCR5⁺ TCF1⁺ progenitor-exhausted T cells. On the other hand, PD-1^high CXCR5-TCF1-terminally differentiated exhausted T cells are thought to be defective and unable to be reactivated. Clinical studies in lung cancer found that TIM-3 expression is elevated after anti-PD-1 therapy, suggesting that TIM-3 may contribute to ICB resistance. Another inhibitory molecule, LAG3, works by attaching to MHCII and inhibiting T cell activation.

Fig 1 The continuous procedure of T cell exhaustion.¹

• Impaired formation of T cell memory

The most compelling clinical evidence for immune checkpoint inhibitors' (ICIs') efficacy is the potential for long-term, long-lasting clinical benefit. To form long-term immunological memory, effector T cells develop into effector memory T cells with the help of helper CD4⁺ T cells and DCs. As a result, ICB therapy may fail due to reduced T cell memory formation. It was discovered that epigenetic changes were capable of limiting the persistence of immunological memory by interfering with T cell memory development in order to reduce the lethal effect on tumor cells. It was also discovered that when tumor antigen remains for an extended period of time, there was limited reacquisition of memory T cell response in patients with a larger tumor burden. As a result, memory effector T cell injury might result in a poor clinical outcome, acquired ICB resistance, or tumor recurrence following medication removal.

• The metabolism of the TME

The TME can be characterized as a low-glucose, hypoxic circumstance. In such conditions, a shortage of glucose hinders T cell activation, reduces antitumor immunity, and develops ICI resistance. Lactate, which is abundant in the low-glucose TME, has been demonstrated to promote PD1 expression in Treg cells and contribute to ICI resistance. Furthermore, mutations in various genes implicated in cancer metabolism, including PI3K, LKB1, and MYC, can lead to resistance. IDO, an enzyme that converts tryptophan to the immunosuppressive chemical kynurenine, has been linked to ICI resistance.

Fig 2 The interaction of CD8⁺T cells with other suppressive cells in the TME.²

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References

1. Nagasaki, Joji et al. "Mechanisms of resistance to immune checkpoint inhibitors." Cancer science vol. 113,10 (2022): 3303-3312.
2. Zhou, Xiaoting et al. "Mechanisms of tumor resistance to immune checkpoint blockade and combination strategies to overcome resistance." Frontiers in immunology vol. 13 915094. 15 Sep. 2022.

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