Abstract 174P
Background
Colorectal cancer (CRC) is the second leading cause of cancer deaths, and liver metastasis accounts for most fatalities in CRC patients. Developing more effective treatments for patients with metastatic CRC is an urgent unmet need. Sphingosine kinase 1 (SPHK1) is selectively expressed in tumor-associated macrophages (TAMs) and SPHK1+ TAMs are abundant in metastatic tumor microenvironment. Here, we aimed to reveal the role of SPHK1+ TAMs in regulating immunosuppression and develop novel therapeutic strategies to enhance the efficacy of immune checkpoint blockade (ICB) therapy and mitigate ICB-induced toxicity.
Methods
The expression of SPHK1 in TAMs was determined using laser scanning microscopy and single-cell sequencing databases. The inhibitory effect of SPHK1 blockade alone or combined with ICB on liver metastasis was assessed using an orthotopic mouse model or intrasplenic injection of tumor cells. Flow cytometry and mass cytometry were used to analyze the immune microenvironment in SPHK1-/- knockout mice. The effect of SPHK1 inhibitor PF543 on the ICB-induced toxicity was verified by DSS-induced colitis or humanized mouse model in a combination of ICB. RNA sequencing and western blot were used to further explore the molecular mechanism by which SPHK1 promoted inflammasome activation and IL-1β release.
Results
SPHK1 was selectively expressed by TAMs in CRC, and the abundance of SPHK1+ TAMs was associated with adverse clinical outcomes in CRC patients. In vivo, SPHK1 knockout and inhibition suppressed liver metastasis of CRC and enhanced the anti-tumor activity of ICB. Blocking SPHK1 reduced the infiltration of TAMs and exhausted T cells, and promoted cytotoxicity of CD8+ T cells. Mechanistically, SPHK1/S1P axis led to IL-1β secretion in response to AIM2 and NLRP3 inflammasome activation. SPHK1 inhibitor PF543 and anti-IL-1R alleviated ICB-induced toxicity, including colitis and liver damage. PF543 plus anti-PD-1 therapy could induce complete regression of liver metastasis and mitigate liver dysfunction when further combined with radiotherapy.
Conclusions
Targeting SPHK1 in macrophages could inhibit liver metastasis of CRC and decouple ICB anti-tumor immunity and toxicity.
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China (No.82103595).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
126P - Evaluation of Myeloid Targeting Agents, PY159 and PY314, in Two Dose Expansion Phase 1b Trials in Platinum-Resistant Ovarian Cancer
Presenter: Oladapo Yeku
Session: Poster Display
116TiP - Randomized, open-label, phase II study of botensilimab (BOT) alone and in combination with balstilimab (BAL) versus standard-of-care in patients with refractory metastatic colorectal cancer
Presenter: Eric Van Cutsem
Session: Poster Display
127P - REGN5668 (MUC16xCD28 bispecific antibody) with cemiplimab (anti-PD-1 antibody) in recurrent ovarian cancer: Phase 1 dose-escalation study
Presenter: Ira Winer
Session: Poster Display
128P - A phase I dose escalation and expansion trial of LYT-200, a Galectin-9 antibody +/- tislelizumab
Presenter: Gerald Falchook
Session: Poster Display
129P - Naxitamab efficacy in patients with refractory/relapsed high-risk neuroblastoma and bone metastases as assessed by Curie score
Presenter: Brian Kushner
Session: Poster Display
131P - Safety and clinical efficacy of Roginolisib (IOA-244), the first oral allosteric modulator of phosphoinositide 3-kinase inhibitor delta (PI3K_)
Presenter: Anna Di Giacomo
Session: Poster Display
132P - A phase I clinical trial of QLS31905 in advanced solid tumors
Presenter: Yakun Wang
Session: Poster Display
133P - Phase 1/2 study of XTX101, a masked, tumor-activated Fc-enhanced anti-CTLA-4, in patients with advanced solid tumors
Presenter: Diwakar Davar
Session: Poster Display
134P - A Phase 1 Study Exploring the Safety and Tolerability of the Small Molecule PD-L1 Inhibitor INCB099318 in Select Advanced Solid Tumors
Presenter: David Pinato
Session: Poster Display
135P - Isunakinra as Monotherapy and Combined with Nivolumab for Treatment Resistant Advanced Solid Tumours: Exploratory Effect Data, Tolerability, and Pharmacokinetics from a Dose Escalation Trial
Presenter: Carlos Becerra
Session: Poster Display