Soluble galectin‐3 as a microenvironment‐relevant immunoregulator with prognostic and predictive value in lung adenocarcinoma

Torres‐Martínez, Susana; Calabuig‐Fariñas, Silvia; Moreno‐Manuel, Andrea; Bertolini, Giulia; Herreros‐Pomares, Alejandro; Escorihuela, Eva; Duréndez‐Saéz, Elena; Guijarro, Ricardo; Blasco, Ana; Roz, Luca; Camps, Carlos; Jantus‐Lewintre, Eloisa

doi:10.1002/1878-0261.13505

Cited by 3 publications

(1 citation statement)

References 97 publications

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“…For instance, in a lung adenocarcinoma tumor sphere-model, which mimic an immunosuppressive TME, galectin-3 is released in the TME and modulated the tumor infiltrating immune cells such as regulatory T cells (Treg) ( 34 ). These authors demonstrated that the patients with high soluble galectin-3 levels had more Treg cells, which can inhibit T cells ( 34 ). Treg are also suggested to inhibit γδ T-cell proliferation ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Vdelta1 T cells are more resistant than Vdelta2 T cells to the immunosuppressive properties of galectin-3

Schadeck,

Oberg,

Peipp

et al. 2024

Front. Immunol.

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Ovarian carcinomas have the highest lethality amongst gynecological tumors. A problem after primary resection is the recurrence of epithelial ovarian carcinomas which is often associated with chemotherapy resistance. To improve the clinical outcome, it is of high interest to consider alternative therapy strategies. Due to their pronounced plasticity, γδ T cells are attractive for T-cell-based immunotherapy. However, tumors might escape by the release of lectin galectin-3, which impairs γδ T-cell function. Hence, we tested the effect of galectin-3 on the different γδ T-cell subsets. After coculture between ovarian tumor cells and Vδ1 or Vδ2 T cells enhanced levels of galectin-3 were released. This protein did not affect the cytotoxicity of both γδ T-cell subsets, but differentially influenced the proliferation of the two γδ T-cell subsets. While increased galectin-3 levels and recombinant galectin-3 inhibited the proliferation of Vδ2 T cells, Vδ1 T cells were unaffected. In contrast to Vδ1 T cells, the Vδ2 T cells strongly upregulated the galectin-3 binding partner α3β1-integrin after their activation correlating with the immunosuppressive properties of galectin-3. In addition, galectin-3 reduced the effector memory compartment of zoledronate-activated Vδ2 T cells. Therefore, our data suggest that an activation of Vδ1 T-cell proliferation as part of a T-cell-based immunotherapy can be of advantage.

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Section: Discussionmentioning

confidence: 99%

Vdelta1 T cells are more resistant than Vdelta2 T cells to the immunosuppressive properties of galectin-3

Schadeck,

Oberg,

Peipp

et al. 2024

Front. Immunol.

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Galectin-3 induces pathogenic immunosuppressive macrophages through interaction with TREM2 in lung cancer

Wang,

Wu,

Jiang

et al. 2024

J Exp Clin Cancer Res

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Background High infiltration of tumor-associated macrophages (TAMs) is associated with tumor promotion and immunosuppression. The triggering receptor expressed on myeloid cells 2 (TREM2) is emerged as a key immunosuppressive regulator for TAMs, however, how TREM2-expressing TAMs are recruited and what ligands TREM2 interacts with to mediate immunosuppression is unknown. Methods Flow cytometry and single-cell RNA sequencing were used to analyze TREM2 expression. Mechanistically, mass spectrometry and immunoprecipitation were employed to identify proteins binding to TREM2. Phagocytosis and co-culture experiments were used to explore the in vitro functions of galectin3-TREM2 pair. Establishment of TREM2f/f-Lyz2-cre mice to validate the role of TREM2 signaling pathway in lung carcinogenesis. GB1107 were further supplemented to validate the therapeutic effect of Galectin3 based on TREM2 signaling regulation. Results This study identified that abundant TREM2+ macrophages were recruited at the intra-tumor site through the CCL2-CCR2 chemotactic axis. Galectin-3 impaired TREM2-mediated phagocytosis and promoted the conversion of TREM2+ macrophages to immunosuppressive TAMs with attenuated antigen presentation and co-stimulatory functions both in vitro both in vivo, and galectin-3 is a potential ligand for TREM2. Genetic and pharmacological blockade of TREM2 and galectin-3 significantly inhibited lung cancer progression in subcutaneous and orthotopic cancer models by remodeling the tumor immune microenvironment. Conclusion Our findings revealed a previously unknown association between galectin-3 and TREM2 in TAMs of lung cancer, and suggested simultaneous inhibition of galectin3 and TREM2 as potent therapeutic approach for lung cancer therapy. Graphical Abstract

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Circulating Immune Proteins: Improving the Diagnosis and Clinical Outcome in Advanced Non-Small Cell Lung Cancer

Torres-Martínez,

Calabuig-Fariñas,

Gallach

et al. 2023

IJMS

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Immunotherapy has been proven a viable treatment option for non-small cell lung cancer (NSCLC) treatment in patients. However, some patients still do not benefit. Finding new predictive biomarkers for immunocheckpoint inhibitor (ICI) response will improve treatment management in the clinical routine. In this regard, liquid biopsy is a useful and noninvasive alternative to surgical biopsies. In the present study, we evaluated the potential diagnostic, prognostic, and predictive value of seven different soluble mediators involved in immunoregulation. Fifty-two plasma samples from advanced NSCLC treated in first-line with pembrolizumab at baseline (PRE) and at first response assessment (FR) were analyzed. In terms of diagnostic value, our results revealed that sFGL1, sGAL-3, and sGAL-1 allowed for optimal diagnostic efficacy for cancer patients. Additionally, the combination of sFGL1 and sGAL-3 significantly improved diagnostic accuracy. Regarding the predictive value to assess patients’ immune response, sCD276 levels at PRE were significantly higher in patients without tumor response (p = 0.035). Moreover, we observed that high levels of sMICB at PRE were associated with absence of clinical benefit (pembrolizumab treatment less than 6 months) (p = 0.049), and high levels of sMICB and sGAL-3 at FR are also related to a lack of clinical benefit (p = 0.027 and p = 0.03, respectively). Finally, in relation to prognosis significance, at PRE and FR, sMICB levels above the 75th percentile are related to poor progression-free survival (PFS) (p = 0.013 and p = 0.023, respectively) and overall survival (OS) (p = 0.001 and p = 0.011, respectively). An increase in sGAL3 levels at FR was associated with worse PFS (p = 0.037). Interestingly, high sGAL-3 at PRE was independently associated with PFS and OS with a hazard ratio (HR) of 2.45 (95% CI 1.14–5.25; p = 0.021) and 4.915 (95% CI 1.89–12.73; p = 0.001). In conclusion, plasma levels of sFGL1, sGAL-3, and sGAL-1 could serve as diagnostic indicators and sMICB, sCD276, and sGAL3 were linked to outcomes, suggesting their potential in assessing NSCLC under pembrolizumab treatment. Our results highlight the value of employing soluble immune biomarkers in advanced lung cancer patients treated with pembrolizumab at first-line.

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Soluble galectin‐3 as a microenvironment‐relevant immunoregulator with prognostic and predictive value in lung adenocarcinoma

Cited by 3 publications

References 97 publications

Vdelta1 T cells are more resistant than Vdelta2 T cells to the immunosuppressive properties of galectin-3

Vdelta1 T cells are more resistant than Vdelta2 T cells to the immunosuppressive properties of galectin-3

Galectin-3 induces pathogenic immunosuppressive macrophages through interaction with TREM2 in lung cancer

Circulating Immune Proteins: Improving the Diagnosis and Clinical Outcome in Advanced Non-Small Cell Lung Cancer

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