Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppression Article Swipe
Sofía Bruni
,
Florencia Mauro
,
Cecilia J. Proietti
,
Rosalía I. Cordo Russo
,
Martín A. Rivas
,
Gloria Inurrigarro
,
Agustina Dupont
,
Darío Rocha
,
Elmer A. Fernández
,
Ernesto Gil Deza
,
Daniel Lopez Della Vecchia
,
Sabrina Barchuk
,
Silvina Figurelli
,
David Lasso
,
Adrián David Friedrich
,
María C Santilli
,
María Victoria Regge
,
Gabriel Lebersztein
,
Claudio Levit
,
Fabiana Anfuso
,
Teresa Castiglione
,
Patricia V. Elizalde
,
María F. Mercogliano
,
Roxana Schillaci
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1136/jitc-2022-005325
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1136/jitc-2022-005325
Background The success of HER2-positive (HER2+) breast cancer treatment with trastuzumab, an antibody that targets HER2, relies on immune response. We demonstrated that TNFα induces mucin 4 (MUC4) expression, which shields the trastuzumab epitope on the HER2 molecule decreasing its therapeutic effect. Here, we used mouse models and samples from HER2+ breast cancer patients to unravel MUC4 participation in hindering trastuzumab effect by fostering immune evasion. Methods We used a dominant negative TNFα inhibitor (DN) selective for soluble TNFα (sTNFα) together with trastuzumab. Preclinical experiments were performed using two models of conditionally MUC4-silenced tumors to characterize the immune cell infiltration. A cohort of 91 patients treated with trastuzumab was used to correlate tumor MUC4 with tumor-infiltrating lymphocytes. Results In mice bearing de novo trastuzumab-resistant HER2+ breast tumors, neutralizing sTNFα with DN induced MUC4 downregulation. Using the conditionally MUC4-silenced tumor models, the antitumor effect of trastuzumab was reinstated and the addition of TNFα-blocking agents did not further decrease tumor burden. DN administration with trastuzumab modifies the immunosuppressive tumor milieu through M1-like phenotype macrophage polarization and NK cells degranulation. Depletion experiments revealed a cross-talk between macrophages and NK cells necessary for trastuzumab antitumor effect. In addition, tumor cells treated with DN are more susceptible to trastuzumab-dependent cellular phagocytosis. Finally, MUC4 expression in HER2+ breast cancer is associated with immune desert tumors. Conclusions These findings provide rationale to pursue sTNFα blockade combined with trastuzumab or trastuzumab drug conjugates for MUC4+ and HER2+ breast cancer patients to overcome trastuzumab resistance.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1136/jitc-2022-005325
- https://jitc.bmj.com/content/jitc/11/3/e005325.full.pdf
- OA Status
- gold
- Cited By
- 19
- References
- 53
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4323543147
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4323543147Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1136/jitc-2022-005325Digital Object Identifier
- Title
-
Blocking soluble TNFα sensitizes HER2-positive breast cancer to trastuzumab through MUC4 downregulation and subverts immunosuppressionWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2023Year of publication
- Publication date
-
2023-03-01Full publication date if available
- Authors
-
Sofía Bruni, Florencia Mauro, Cecilia J. Proietti, Rosalía I. Cordo Russo, Martín A. Rivas, Gloria Inurrigarro, Agustina Dupont, Darío Rocha, Elmer A. Fernández, Ernesto Gil Deza, Daniel Lopez Della Vecchia, Sabrina Barchuk, Silvina Figurelli, David Lasso, Adrián David Friedrich, María C Santilli, María Victoria Regge, Gabriel Lebersztein, Claudio Levit, Fabiana Anfuso, Teresa Castiglione, Patricia V. Elizalde, María F. Mercogliano, Roxana SchillaciList of authors in order
- Landing page
-
https://doi.org/10.1136/jitc-2022-005325Publisher landing page
- PDF URL
-
https://jitc.bmj.com/content/jitc/11/3/e005325.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
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https://jitc.bmj.com/content/jitc/11/3/e005325.full.pdfDirect OA link when available
- Concepts
-
Trastuzumab, Medicine, Breast cancer, Cancer research, Immune system, Immunology, Cancer, Internal medicineTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
19Total citation count in OpenAlex
- Citations by year (recent)
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2025: 7, 2024: 8, 2023: 4Per-year citation counts (last 5 years)
- References (count)
-
53Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| institutions_distinct_count | 24 |
| corresponding_institution_ids | https://openalex.org/I151201029, https://openalex.org/I71650599 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.8399999737739563 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.95902415 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |