Combining precision oncology and immunotherapy by targeting the MALT1 protease

Abstract

An innovative strategy for cancer therapy is to combine the inhibition of cancer cell-intrinsic oncogenic signaling with cancer cell-extrinsic immunological activation of the tumor microenvironment (TME). In general, such approaches will focus on two or more distinct molecular targets in the malignant cells and in cells of the surrounding TME. In contrast, the protease Mucosa-associated lymphoid tissue protein 1 (MALT1) represents a candidate to enable such a dual approach by engaging only a single target. Originally identified and now in clinical trials as a lymphoma drug target based on its role in the survival and proliferation of malignant lymphomas addicted to chronic B cell receptor signaling, MALT1 proteolytic activity has recently gained additional attention through reports describing its tumor-promoting roles in several types of non-hematological solid cancer, such as breast cancer and glioblastoma. Besides cancer cells, regulatory T (Treg) cells in the TME are particularly dependent on MALT1 to sustain their immune-suppressive functions, and MALT1 inhibition can selectively reprogram tumor-infiltrating Treg cells into Foxp3-expressing proinflammatory antitumor effector cells. Thereby, MALT1 inhibition induces local inflammation in the TME and synergizes with anti-PD-1 checkpoint blockade to induce antitumor immunity and facilitate tumor control or rejection. This new concept of boosting tumor immunotherapy in solid cancer by MALT1 precision targeting in the TME has now entered clinical evaluation. The dual effects of MALT1 inhibitors on cancer cells and immune cells therefore offer a unique opportunity for combining precision oncology and immunotherapy to simultaneously impair cancer cell growth and neutralize immunosuppression in the TME. Further, MALT1 targeting may provide a proof of concept that modulation of Treg cell function in the TME represents a feasible strategy to augment the efficacy of cancer immunotherapy. Here, we review the role of MALT1 protease in physiological and oncogenic signaling, summarize the landscape of tumor indications for which MALT1 is emerging as a therapeutic target, and consider strategies to increase the chances for safe and successful use of MALT1 inhibitors in cancer therapy.

Translational Studies Using the MALT1 Inhibitor (S)-Mepazine to Induce Treg Fragility and Potentiate Immune Checkpoint Therapy in Cancer

“…The fact that such partial inhibition produced pronounced antitumor effects parallels prior observations whereby a partial reduction of CARMA1 protein was sufficient to reprogram tumor-infiltrating Tregs but did not affect Tregs elsewhere or cause autoimmune disease. [ 34 - 61 ] This supports the concept that incomplete target occupancy is desirable in the use of MALT1 inhibitors for the immunotherapy of cancer, especially because it will also minimize any potential immune-suppressive effects on effector lymphocytes that could mitigate the antitumor immune response.…”

Comprehensive analysis of basement membrane‐related gene based on single‐cell and bulk RNA sequencing data to predict prognosis and evaluate immune characteristics in colorectal cancer

“…An escalating number of studies underscore the tumor‐related ECM as a significant impediment to achieving enhanced success in cancer immunotherapy cases 31,32 . Multiple investigations have delineated that the tumor‐related extracellular matrix (ECM) actively propels the processes of tumor cell growth, invasion, metastasis, and angiogenesis, while simultaneously thwarting programmed cell death and impeding drug diffusion 33,34 . Consequently, gaining an in‐depth understanding of the intricate interplay between ECM and the tumor immune response is essential for realizing the potential of targeting the tumor‐associated ECM to enhance the efficacy of cancer immunotherapy.…”

MALT1 substrate cleavage: what is it good for?

“…MALT1 protease function is also implicated in the growth of several non-hematologic solid cancers. Potent and selective MALT1 inhibitors have been developed, which are currently undergoing pre-clinical and clinical evaluation for the treatment of MALT1-dependent non-Hodgkin’s lymphoma, but also for depleting suppressive Treg cells in the tumor microenvironment to enhance anti-tumor immunity ( 24 – 26 ). In addition, defective or aberrant MALT1 protease activation has been implicated in human immune errors of immunity caused by germline mutations in CBM components, which have been associated with various immune pathologies such as immunodeficiency, atopy and B cell lymphocytosis ( 27 , 28 ).…”