Inhibition of Cbl-b restores effector functions of human intratumoral NK cells.

in Journal for immunotherapy of cancer by Sofia Tundo, Marcel Trefny, Andrijana Rodić, Olivia Grueninger, Nicole Brodmann, Anastasiya Börsch, Clara Serger, Jonas Fürst, Melanie Buchi, Katarzyna Buczak, Alex T Müller, Lisa Sach-Peltason, Leyla Don, Petra Herzig, Didier Lardinois, Viola Heinzelmann-Schwarz, Kirsten D Mertz, Aljaž Hojski, Karin Schaeuble, Heinz Laubli, Marina Natoli, Alberto Toso, Thuy T Luu, Alfred Zippelius, Andrea Romagnani

TLDR

  • The study is looking at how to make the immune system better at fighting cancer. They found a way to make a type of immune cell called NK cells work better. They did this by finding a drug that makes the NK cells more active. They also found that this drug can work with another drug to make the NK cells even more active. This could help improve outcomes for patients with cancer.

Abstract

T cell-based immunotherapies including immune checkpoint blockade and chimeric antigen receptor T cells can induce durable responses in patients with cancer. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of natural killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their major histocompatibility complex class I (MHC I) expression due to acquired resistance mechanisms.However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy. In this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compounds on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated using compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types. The screening approach led to the identification of a Casitas B-lineage lymphoma (Cbl-b) inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells. These findings underscore the relevance of Cbl-b inhibition in overcoming NK cell dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for patients with cancer.

Overview

  • The study focuses on the potential of natural killer (NK) cells in cancer immunotherapy. The authors conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. The screening approach led to the identification of a Casitas B-lineage lymphoma (Cbl-b) inhibitor enhancing the activity of primary human NK cells. The study aims to investigate the effect of the top performing compounds on dysfunctional NK cells generated by a newly developed in vitro platform and validate the findings on patient-derived intratumoral dysfunctional NK cells from different cancer types. The primary objective of the study is to identify a Cbl-b inhibitor that can reinvigorate the activity of dysfunctional NK cells and improve outcomes for patients with cancer.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions. The authors found that the Casitas B-lineage lymphoma (Cbl-b) inhibitor enhanced the activity of primary human NK cells. The Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Furthermore, Cbl-b inhibition combined with T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells. The key findings of the study suggest that Cbl-b inhibition can complement existing immunotherapies and improve outcomes for patients with cancer.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The identification of a Cbl-b inhibitor that can reinvigorate the activity of dysfunctional NK cells holds potential for bolstering cancer immunotherapy. The study suggests that Cbl-b inhibition can complement existing immunotherapies and improve outcomes for patients with cancer. Future research directions could focus on the development of combination therapies that incorporate Cbl-b inhibition with other immunotherapies or targeted therapies to further enhance the efficacy of cancer immunotherapy.
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