INNATE IMMUNE SIGNALING
Targeting DDR factors in cancer cells can enhance anti-tumor immune responses by inducing cancer-intrinsic innate immune signaling. This signaling cascade is initiated by pattern-recognition receptors, such as cGAS, which senses cytosolic DNA and activates STING, eliciting the expression of type I interferons (e.g., IFN-α and IFN-β) by interferon regulatory factors (IRFs) and NF-κB, followed by JAK/STAT-dependent expression of cytokines and other interferon-stimulated genes (ISGs) (Jenson and Chen, Mol Cell, 2024; Figure 8). Consequently, the secretion of IFNs and ISGs into the tumor microenvironment by cancer cells can facilitate tumor antigen presentation and promote the recruitment and activation of cytotoxic T cells that mediate tumor rejection (Samson and Ablasser, Nat Cancer, 2022).
Figure 8. Simplified schematic of innate immune signaling induced by genome instability
PD-(L)1-MEDIATED IMMUNE CHECKPOINT RESPONSE
Tumor cells employ multiple immuno-suppressive mechanisms to counteract the activation of cancer-intrinsic innate immunity. For example, in response to IFN signaling resulting from chemotherapy- and radiotherapy-induced DNA damage, or DNA repair inhibition, cancer cells can evade immunity by overexpressing the immune checkpoint regulator PD-L1 (Klapp et al, Cancer Discovery, 2023), which can bind the PD-1 receptor on cytotoxic T cells, limiting their ability to kill cancer cells (Sun et al, Immunity, 2018; Figure 9).
Immune checkpoint blockade (ICB) therapies targeting PD-(L)1 can induce robust responses against numerous cancer types (Sharma et al, Cell, 2023). However, tumors often employ immunosuppressive mechanisms to attain ICB resistance, limiting the efficacy of ICB therapies (Schoenfeld et al, Cancer Cell, 2020).
Figure 9. Induction of the PD-L1 immune checkpoint regulator in response to interferon signaling
Characterization of DDR factors that regulate innate immune signaling and the PD-L1 immune checkpoint
To study the interplay between innate immune signaling and immune checkpoint responses, we performed a FACS-based CRISPR-Cas9 screen targeting DDR factors and chromatin regulators using as a readout dual staining for PD-L1 and the nuclear fraction of the IRF3 transcription factor, a marker of cell-intrinsic innate immune activation (Leuzzi et al, Cell, 2024). Through this approach, we identified the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses (Figure 10). Mechanistically, SMARCAL1 limits endogenous DNA damage, thereby suppressing cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a PD-L1 transcriptional regulatory element, thereby promoting PD-L1 expression in cancer cells (Figure 10). SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncovered SMARCAL1 as a promising target for cancer immunotherapy.
Figure 10. SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion