Abstract 1656: Effects of chemotherapy on activation of the STING signaling pathway and enhancing immunotherapy responses in colorectal cancer
Authors: Fan Fan , Ghosh Susmita , Ellis Lee , Bhattacharya Rajat 
Published: July 2021

Background: Metastatic colorectal cancer (mCRC) is the second leading cause of cancer death in the US. The response rate to current systemic therapies is ~50% and most patients die within 2.5 years from the diagnosis of metastasis. Recently, immune checkpoint inhibitor (ICI) therapies have shown benefit in a small subset (~4%) of patients with mCRC whose tumors were microsatellite instability-high (MSI-H), in contrast to those patients with mCRCs that are microsatellite stable (MSS) where responses are extremely rare. Thus, developing therapeutic approaches to improve the efficacy of ICI therapies in patients with MSS mCRC is extremely important.

Aims: Our aim was to identify strategies that can likely increase immune-cell infiltration in MSS CRC as one of the major factors responsible for patients with MSI-H mCRC to respond to ICI therapies is high levels of immune-cell infiltration in the tumors.

Methods and Results: Recent studies have shown that activation of the STimulator of INterferon Genes (STING) innate immune pathway results in alterations in cytokine release from cancer cells that, in turn, lead to enhanced recruitment of T-cells in the tumor microenvironment. Thus, activation of STING is likely a means of overcoming resistance to ICI-therapy. We hypothesized that activating the STING pathway, via specific cytotoxic chemotherapeutic agents, could result in improved clinical responses in patients with MSS mCRC. We treated a panel of MSI-H and MSS CRC cell lines with various chemotherapies approved for the treatment of patients with mCRC. STING protein was found to be activated in all cell lines treated with SN38, the active metabolite of irinotecan, but not with oxaliplatin or 5FU. Using western blot analyses, we demonstrated a significant increase in STING protein and its polymerization in CRC cells treated with SN38. Activation of factors downstream of STING signaling was also observed in SN38 treated CRC cells. Finally, performing migration assays using the macrophage cell line THP-1 demonstrated that conditioned media (CM) from CRC cells treated with SN38 could significantly increase migration of THP-1 cells when compared to CM from untreated CRC cells.

Conclusions: Our studies indicate that among the three major chemotherapies that are used for treatment of patients with mCRC, SN38 has the strongest effect on activation of the STING pathway in both MSI-H and MSS CRC cells. SN38 treatment of CRC cells results in induction of an immune-modulatory secretome leading to increased migration of immune-cells. These findings indicate that specific chemotherapies can likely modulate ICI-therapy responses and further in depth studies evaluating the efficacy of combining SN38 and ICI therapies in MSS mCRC are warranted.

Citation Format: Fan Fan, Susmita Ghosh, Lee Ellis, Rajat Bhattacharya. Effects of chemotherapy on activation of the STING signaling pathway and enhancing immunotherapy responses in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1656.