What question did this study set out to answer?

The research aims to explore the role of the SPHK1/S1P axis in regulating B cell function and its implications for cancer immunotherapy.

April 5, 2026

Abstract 7941: The Sphk1-B cell axis as a targetable immunoregulatory pathway in cancer

Key Points

The research aims to explore the role of the SPHK1/S1P axis in regulating B cell function and its implications for cancer immunotherapy.
Utilized murine cancer models (ovarian, melanoma, colorectal) with SPHK1 gene deletion.
Assessed tumor burden and immune cell infiltration post SPHK1 knockout.
Conducted flow cytometry and immunohistochemistry for immune profiling.
Analyzed metabolic changes in B cells due to SPHK1 deficiency.
Tested pharmacologic SPHK1 inhibition to evaluate effects on B cell activation.
SPHK1 deficiency resulted in significantly reduced tumor burden and S1P levels.
Increased infiltration of CD19+ B cells and other lymphocytes in tumors of SPHK1-/- mice.
Enhanced metabolic markers related to plasma cell differentiation were observed.
Pharmacologic inhibition of SPHK1 mimicked genetic knockout effects on B cell functions.
Targeting SPHK1 promoted antibody-mediated anti-tumor immunity.

Abstract

Abstract Background: The sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling axis regulates tumor progression and immune suppression within the tumor microenvironment (TME). While SPHK1-mediated S1P generation is known to promote ovarian cancer growth, its role in shaping B cell-driven anti-tumor immunity remains unclear. Methods and Results: Genetic ablation of SPHK1 (SPHK1-/-) in murine ovarian cancer (ID8 Trp53-/-; Brca2-/-), melanoma (B16F10), and colorectal cancer (MC38) models resulted in markedly reduced tumor burden accompanied by ∼50% reduction in S1P levels. Tumors from SPHK1-/- mice demonstrated increased immune infiltration, primarily B and T lymphocytes, and enrichment of immunoglobulin-related and antigen presentation gene signatures. Flow cytometry and IHC confirmed enhanced tumor-infiltrating CD19+ B cells, plasma cells, and upregulation of activation and antigen-presentation markers (CD69, CD80, CD86, CD40, MHC-II).Mechanistically, SPHK1 deficiency promoted metabolic reprogramming that supported plasma cell differentiation, characterized by elevated unfolded protein response (XBP1, BiP, GRP94), increased oxidative phosphorylation, ATP generation, mitochondrial biogenesis, and FOXO1 activation. Pharmacologic SPHK1 inhibition using PF543 phenocopied genetic knockout, increasing plasma cell frequency, immunoglobulin secretion, and activation-associated transcriptional programs. Taken together, our data suggest that SPHK1 inhibition activates B cells for enhanced anti- tumor immune response. Conclusion: SPHK1/S1P axis inhibition reprograms B cells toward robust metabolic fitness, plasma cell differentiation, and antibody-mediated anti-tumor immunity. Targeting SPHK1 represents a promising strategy to boost humoral immunity and overcome immune-excluded ovarian cancer phenotypes. Impact: This study uncovers a previously unrecognized immunometabolism by which SPHK1 controls B cell function, highlighting its therapeutic potential for enhancing anti-tumor immunity and improving immunotherapy responsiveness. Citation Format: Mona Singh, Prachi Gupta, Arezou Rahimi, Sunila Pradeep. The Sphk1-B cell axis as a targetable immunoregulatory pathway in cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7941.

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