Oncolytic Virotherapy and Microenvironment in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of bone marrow (BM) clonal plasma cells, which are strictly dependent on the microenvironment. Despite the improvement of MM survival with the use of new drugs, MM patients still relapse and become always refractory to the treatment. The development of new therapeutic strategies targeting both tumor and microenvironment cells are necessary. Oncolytic virotherapy represent a promising approach in cancer treatment due to tumor-specific oncolysis and activation of the immune system. Different types of human viruses were checked in preclinical MM models, and the use of several viruses are currently investigated in clinical trials in MM patients. More recently, the use of alternative non-human viruses has been also highlighted in preclinical studies. This strategy could avoid the antiviral immune response of the patients against human viruses due to vaccination or natural infections, which could invalid the efficiency of virotherapy approach. In this review, we explored the effects of the main oncolytic viruses, which act through both direct and indirect mechanisms targeting myeloma and microenvironment cells inducing an anti-MM response. The efficacy of the oncolytic virus-therapy in combination with other anti-MM drugs targeting the microenvironment has been also discussed.

TGF-β: an active participant in the immune and metabolic microenvironment of multiple myeloma

“…NK cells can directly kill cells without relying on antibodies and complement via the production of IFN-γ [56]. but may shift, termed "Th1/Th2 drift", potentially leading to diseases, including cancers [65]. TGF-β influences Th2 cells by impeding activation through TCR signaling inhibition and downregulating crucial transcription factors like T-bet and GATA3, pivotal for Th2 cell differentiation [49,54,56,63].…”

“…Th1/Th2 cells maintain equilibrium efficiently, while mature DCs activate T cells, orchestrating immune reactions. However, MDSCs and certain cytokines from myeloma cells like IL-6, IL-10, and TGF-β [19,65]. TGF-β in the TME induces an immune-suppressive DC phenotype by upregulating ID1 via the TGF-β/SMAD pathway [49,57].…”

“…There [51,54]. In MM's TME, elevated TGF-β and IL-6 levels prompt CD4 + Tregs to inhibit immune surveillance and reduce effector T cells [8,65]. Tregs secrete IL-10, fostering MM development [53], while IL-10 activates TGF-β [19].…”

“…However, immunosuppressive elements like MDSCs and M2-TAMs in the TME of MM often hinder CTLs and NK cells. TGF-β is known to inhibit CTLs [54,65]. TGF-β inhibits TCR signaling and suppresses Myc and Jun genes, halting CTL proliferation [49].…”

Comparação entre a eficácia da imunoterapia e da viroterapia oncolítica no tratamento do câncer hematológico: síntese de evidências

“…Vale salientar que o principal tumor hematológico que tem obtido melhora com o uso de viroterapia é o mieloma múltiplo; porém, para melhores resultados, é necessário associar o tratamento da viroterapia com outros procedimentos. Vale lembrar que não há, na literatura, dados bem estabelecidos acerca da taxa de resposta ao tratamento do cancer hematológico com a viroterapia (MARCHICA et al, 2021).…”