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B Cells EV-Mediated Signaling in Melanoma


Al Hrout, Alaa. B Cells EV-Mediated Signaling in Melanoma. 2024, University of Zurich, Faculty of Science.

Abstract

The important role of T cells in antitumor immunity has long been established, as their
contribution to antitumor immunity is well documented. Nonetheless, B cells are central in the
humoral response and aiding in antitumor immunity. Conflicting reports on the role of B cells
in tumor response have delayed the acknowledgment of their active contribution in shaping a
positive outcome and optimal anti-immune response. The contradiction can be explained by
the presence of diverse subpopulations of B cells that exercise a vast range of functions.

In melanoma, the presence of B cells in tumors of patients at baseline was correlated with
positive outcomes after ICB therapy. Co-localization of CD8+ T cells and B cells in patient
tumors was linked to improved survival, independently of other clinical variables. This
suggests that B cells could be a promising predictor that distinguishes immunotherapy
responders from non-responders before therapy which was thought to be an exclusive ability
of T cells. Due to their localization, tumor-associated B cells' far-reaching effect has been
under question. We surmise that part of that communication can be accomplished through EV-
mediated signaling, allowing B cells to mediate their effect by proxy.

Available models to study EVs-mediated signaling are limited in the insight they can provide,
especially in the context of immunotherapy. The human immune TME is challenging to
replicate in animal models, creating a xenogeneic TME that fails to encapsulate relevant
aspects of the human adaptive immune response, and are unsuccessful in replicating patient
therapy response. Hence, the most informative approach to study human patients is through
human patient-derived materials. As such, I relied on melanoma patients' biopsies, which are
divided into responders and non-responders to ICB therapy.

We were able to show that in situ EVs (tumor-tissue resident) faithfully recapitulated the TME,
clustering ICB therapy responders and non-responders into 2 cohorts based on their EVs
surface markers and miRNA cargo. The top “signature” miRNA in B cell-derived EVs from
responders was identified as miR-99a-5p, a well-established tumor suppressor in several
cancers. miR-99a-5p exhibited a B cell-dependent phenotype through several arms: 1) it
regulates B cells activation and homeostasis of pro- and anti-tumor B cells, 2) it promotes non-
homologous end joining over homologous recombination repair pathway, 3) it promotes class-
switch recombination, where all aforementioned mechanisms culminate in improved anti-
tumor response and cancer targeting.

Collectively, I was able to show in my thesis, the indispensable role of B cells in anti-tumor
immunity. In addition, B cells are central in the immunotherapy response, and play an
indisputable role in shaping the immune response in the context of ICB therapy.

Abstract

The important role of T cells in antitumor immunity has long been established, as their
contribution to antitumor immunity is well documented. Nonetheless, B cells are central in the
humoral response and aiding in antitumor immunity. Conflicting reports on the role of B cells
in tumor response have delayed the acknowledgment of their active contribution in shaping a
positive outcome and optimal anti-immune response. The contradiction can be explained by
the presence of diverse subpopulations of B cells that exercise a vast range of functions.

In melanoma, the presence of B cells in tumors of patients at baseline was correlated with
positive outcomes after ICB therapy. Co-localization of CD8+ T cells and B cells in patient
tumors was linked to improved survival, independently of other clinical variables. This
suggests that B cells could be a promising predictor that distinguishes immunotherapy
responders from non-responders before therapy which was thought to be an exclusive ability
of T cells. Due to their localization, tumor-associated B cells' far-reaching effect has been
under question. We surmise that part of that communication can be accomplished through EV-
mediated signaling, allowing B cells to mediate their effect by proxy.

Available models to study EVs-mediated signaling are limited in the insight they can provide,
especially in the context of immunotherapy. The human immune TME is challenging to
replicate in animal models, creating a xenogeneic TME that fails to encapsulate relevant
aspects of the human adaptive immune response, and are unsuccessful in replicating patient
therapy response. Hence, the most informative approach to study human patients is through
human patient-derived materials. As such, I relied on melanoma patients' biopsies, which are
divided into responders and non-responders to ICB therapy.

We were able to show that in situ EVs (tumor-tissue resident) faithfully recapitulated the TME,
clustering ICB therapy responders and non-responders into 2 cohorts based on their EVs
surface markers and miRNA cargo. The top “signature” miRNA in B cell-derived EVs from
responders was identified as miR-99a-5p, a well-established tumor suppressor in several
cancers. miR-99a-5p exhibited a B cell-dependent phenotype through several arms: 1) it
regulates B cells activation and homeostasis of pro- and anti-tumor B cells, 2) it promotes non-
homologous end joining over homologous recombination repair pathway, 3) it promotes class-
switch recombination, where all aforementioned mechanisms culminate in improved anti-
tumor response and cancer targeting.

Collectively, I was able to show in my thesis, the indispensable role of B cells in anti-tumor
immunity. In addition, B cells are central in the immunotherapy response, and play an
indisputable role in shaping the immune response in the context of ICB therapy.

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Additional indexing

Item Type:Dissertation (cumulative)
Referees:Chahwan Richard, Baumgartner Martin, Levesque Mitchell Paul
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
UZH Dissertations
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Language:English
Place of Publication:Zürich
Date:20 February 2024
Deposited On:20 Feb 2024 11:38
Last Modified:22 Feb 2024 12:23
Number of Pages:119
OA Status:Closed
  • Content: Published Version
  • Language: English
  • Permission: Download for Admins
  • Embargo till: 2025-01-16