Researchers Discover Important Anti-cancer Target that Activates Innate Immunity and Blocks PD-1/L1 Pathway

Cancer cells use various tricks to achieve immune evasion. For example, a recent research result published by a Columbia University team in Cell found that cancer cells use the same regulatory factor to suppress anti-tumor immune responses through two different mechanisms.

Figure 1. The DNA translocase SMARCAL1 favors tumor immune evasion by two distinct mechanisms. (Leuzzi G, et al., 2024)

This study shows that SMARCAL1, a regulatory factor involved in DNA damage response, can not only help cancer cells maintain genome stability and inhibit the downstream innate immune response activated by the cGAS-STING pathway, but also cooperate with the transcription factor AP-1 family member protein JUN to regulate the upregulation of PD-L1 expression levels in cancer cells at the epigenetic level. From the perspective of anti-cancer treatment, using SMARCAL1 as a therapeutic target can also effectively activate anti-cancer immunity.

Everyone should be familiar with the principle of "synthetic lethality" of PARP inhibitors, which target specific DNA damage repair factors so that cancer cells cannot successfully repair DNA damage, and they may "kill themselves." In the era of cancer immunotherapy, targeting DNA damage repair factors has another value: even if cancer cells do not directly self-destruct, increased genomic instability may activate innate immune response mechanisms such as the cGAS-STING pathway.

The starting point of the Columbia team's research does not stop there. The researchers hope to find a DNA damage repair factor that not only regulates the body's innate anti-tumor immune response but also affects the expression level of PD-L1. Previous studies have found that PARP inhibitor treatment can increase the expression level of PD-L1 in cancer cells, which facilitates combined treatment.

Using CRISPR-Cas9 technology, researchers began to screen targets related to both PD-L1 expression levels and levels of innate immune activation marker and transcription factor IRF3 in triple-negative breast cancer (TNBC) cell lines. A total of 22 potential targets whose expression was enriched in cells with high IRF3 expression and low PD-L1 expression were found, including SMARCAL1. SMARCAL1 knockout does have a dual effect: while the expression level of PD-L1 in cancer cells decreases, IRF3 is also induced and activated, indicating active innate immunity. Changes in levels of interferon-stimulated genes (ISGs) and various cytokines may also serve as evidence.

Further analysis showed that SMARCAL1 knockout indeed exacerbated the instability of the cancer cell genome, including spontaneous DNA breaks, chromatin bridges, increased micronuclei formation, etc. The micronuclei will be recognized by the intracellular cytoplasmic DNA sensor cGAS, thereby activating a cGAS-STING-dependent innate anti-tumor immune response.

The effect of SMARCAL1 on PD-L1 expression levels involves chromatin accessibility at the epigenetic level, which is relatively independent of its involvement in DNA damage response. After SMARCAL1 knockout, three key regulatory regions on the chromatin of the PD-L1 gene, especially the P3 region that upregulates PD-L1 expression, will no longer be accessible, which means that SMARCAL1 can induce upregulation of PD-L1 expression in cancer cells. For SMARCAL1 to play this role, it not only needs to retain its own ATPase activity, but also needs to cooperate with the transcription factor AP-1 family member protein JUN.

Figure 2. Regulation of PD-L1 expression by SMARCAL1. (Leuzzi G, et al., 2024)

Mouse experimental results also show that SMARCAL1 knockout mainly activates the anti-tumor immune response led by CD8+ T cells, and the activation of the cGAS-STING pathway and the decrease in PD-L1 expression levels are indispensable. On the basis of SMARCAL1 knockout, further combination with immune checkpoint inhibitors (anti-PD-L1 or CTLA-4 monoclonal antibodies) can achieve synergistic effects. Data from a database of human cancer patients also confirmed that SMARCAL1 expression levels were indeed lower in patients who responded to immunotherapy.

Reference

Leuzzi G, et al. SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion. Cell, 2024.