MALT1 inhibition suppresses T-cell dependent immune surveillance

• MALT1 supports the development of natural regulatory T cells (Tregs), while protease-dead MALT1 (MALT1-PD) mice develop autoimmunity and an intrinsic capacity to reject syngeneic tumor transplantation. Herein, a small molecule inhibitor targeting MALT1 was developed and evaluated for potential use in Treg inhibition as part of a cancer immunotherapy strategy.In vitro, MALT1 inhibitor treatment inhibited the proteolytic cleavage of the MALT1 substrate HOIL1 in Jurkat cells and blocked IL-2 secretion by immune cells. Moreover, orally administrated MV088428 inhibited anti-CD3 induced IL-2 release in vivo. In vitro MALT1 inhibition selectively suppressed the proliferation of PBMC derived CD25+ FoxP3+ CD4+ T cells, while no direct effect was noted on the proliferation and viability of CD25- CD4+ T cells. In vivo, no evident anti-tumor effect as a monotherapy in the MB49 bladder cancer model was achieved and despite selective decrease of Treg frequencies in lymph nodes of tumor bearing animals, intratumoral Treg depletion was not observed. No synergistic anti-tumor effects were noted when MALT1 inhibitor was combined with anti-PD1 therapy, and concomitant treatment with MALT1 inhibitor abrogated the efficacy of anti-CTLA4 therapy. MALT1 inhibition had no impact on the frequencies of viable NK, lymphocyte and myeloid cells or on proliferation of conventional CD4 and CD8 T cells. However, there was a significant decrease of antigen-specific T cells in vivo upon adoptive T cell transfer and peptide vaccination. Thus, while MALT1 inhibition substantially reduced Treg populations in lymph nodes, but less so in tumors, off-target effects on antigen-experienced T cells along with the lack of impact on tumor Tregs likely abolish the compound’s efficacy. The off-target effect on antigen-experienced T cells could present implications for the use of MALT1 inhibitors for cancer indications where tumor control is likely to be mediated via T cell driven immune surveillance. Thus, dosing length and combination therapy strategies should be carefully designed and evaluated further.

Ämnesord

NATURVETENSKAP  -- Biologi -- Immunologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Immunology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

Nyckelord

Immunologi

Immunology

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