Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer and the second cause of cancer mortality worldwide. The 5-year survival rate is only 12-14% in patients with metastatic CRC . KRAS mutation accounts for 30-50% of human CRC, and its presence correlates positively with disease aggressiveness and metastasis [2, 3]. Anti-EGFR antibodies, such as cetuximab or panitumumab, in combination with chemotherapy are effective therapeutic approaches for metastatic CRC patients with KRAS wild-type. However, the clinical efficacy for KRAS mutant CRC patients is often poor due to the intrinsic drug resistance by KRAS mutation . In recent years, immunotherapy exhibited excellent efficacy for CRC, while it shows poor response for KRAS mutant CRC, emphasizing treatment of these subpopulation patients remains a challenge. Recently, the combination of AMG510 and anti-PD-1 contributes durable anti-tumor response, which indicates that combination therapy may provide a promising treatment option for KRAS mutant CRC subpopulations.
The Homeobox (HOX) family of transcription factors is known to play key roles in embryonic development and regulates many aspects of cellular processes . In recent years, mounting evidence has showed that dysregulation of HOX gene facilities cancer initiation and progression through different mechanism . In mammals, HOX family comprises 39 proteins, which was classified to four separate clusters (A, B, C and D). HOXA subfamily genes are critical regulators in cancer metastasis. Several studies reported that HOXA7, a member of HOXA subfamily, function as an oncogene and contributes to malignant behaviors in kinds of human cancer, including hepatocellular carcinoma , laryngeal squamous cell cancer , ovarian cancer . However, little is known about the role of HOXA7 in CRC metastasis.
Immunosuppression observed during cancer development and progression is a result of the orchestration of many cell types, including MDSCs. The accumulation of relatively immature and pathologically activated MDSCs with potent immunosuppressive activity is common in tumors. Mounting data have shown the accumulation of MDSCs, which induce local and possibly immunosuppression, is correlated with tumor progression . In addition, MDSCs can directly promote tumor cell survival, angiogenesis, invasion and metastasis . MSI-L CRC is more extensively infiltrated by Tregs and MDSCs, while T cells are significantly reduced, which is considered to be the main reason for the poor efficacy of immune checkpoint blocking [13, 14]. Previous study had revealed that for KRAS mutant CRC and KRAS wild types CRC, there is a significant difference in infiltration of immune cells and expression of immune-related molecules. For example, KRAS mutant CRC displays the feature of reduced T helper 1 (Th1)-centric coordinated immune response cluster, and reduced infiltration of cytotoxic cells . The MDSCs infiltration was significantly increase, and depleted MDSCs can significantly improve the efficacy of anti-PD-L1[16, 17]. Whereas the haptic ongenic signal in KRAS mutant CRC that drives MDSCs recruitment and activation remains poorly understood.
Here, we demostrated that HOXA7 was upregulation and associated with poor prognosis in KRAS mutant CRC. Ovexpression of HOXA7 promoted KRAS mutant CRC metastasis by upregulating CXCL1. The administration of CXCR2 inhibitor SB265610 and anti-PD-L1 markedly suppressed HOXA7-mediated KRAS mutant CRC metastasis.