Targeting myeloid-derived suppressor cells in combination with tumor cell vaccination predicts anti-tumor immunity and breast cancer dormancy: an in silico experiment

Abstract

Among the different breast cancer subsets, triple-negative breast cancer (TNBC) has the worst prognosis and limited options for targeted therapies. Immunotherapies are emerging as novel treatment opportunities for TNBC. However, the surging immune response elicited by immunotherapies to eradicate cancer cells can select resistant cancer cells, which may result in immune escape and tumor evolution and progression. Alternatively, maintaining the equilibrium phase of the immune response may be advantageous for keeping a long-term immune response in the presence of a small-size residual tumor. Myeloid-derived suppressor cells (MDSCs) are activated, expanded, and recruited to the tumor microenvironment by tumor-derived signals and can shape a pro-tumorigenic micro-environment by suppressing the innate and adaptive anti-tumor immune responses. We recently proposed a model describing immune-mediated breast cancer dormancy instigated by a vaccine consisting of dormant, immunogenic breast cancer cells derived from the murine 4T1 TNBC-like cell line. Strikingly, these 4T1-derived dormant cells recruited fewer MDSCs compared to aggressive 4T1 cells. Recent experimental studies demonstrated that inactivating MDSCs has a profound impact on reconstituting immune surveillance against the tumor. Here, we developed a deterministic mathematical model for simulating MDSCs depletion from mice bearing aggressive 4T1 tumors resulting in immunomodulation. Our computational simulations indicate that a vaccination strategy with a small number of tumor cells in combination with MDSC depletion can elicit an effective immune response suppressing the growth of a subsequent challenge with aggressive tumor cells, resulting in sustained tumor dormancy. The results predict a novel therapeutic opportunity based on the induction of effective anti-tumor immunity and tumor dormancy.

Triple Negative Breast Cancer: Molecular Subtype-Specific Immune Landscapes with Therapeutic Implications

“…Delving further, there are prospective avenues yet to be explored, suggesting potential interventions based on the observed TIME heterogeneity across different molecular subtypes of TNBC. In the case of LAR tumors, MDSC-targeted therapies could be of potential value, including inhibition of MDSC function or recruitment into the TIME, inducing their differentiation or mediating their depletion [ 56 , 57 ]. In patients with the MSL subtype, featuring a high number of M2 TAMs, inhibition of the chemokine (C-C motif) ligand 2 (CCL2)/circulating chemokine-receptor-type 2 (CCR2) axis could decrease the recruitment of bone marrow mononuclear cells, subsequently reducing macrophage infiltration in the breast [ 58 , 59 ].…”

Navigating the Immune Maze: Pioneering Strategies for Unshackling Cancer Immunotherapy Resistance

“…They excel in restraining CTLs and NK cells, thus curtailing the NK cells' tumor-eradicating capabilities [43,71,72]. Additionally, the MDSCs foster Treg proliferation, intensifying the suppressive milieu [73,74].…”

Hesperidin suppressed metastasis, angiogenesis and tumour growth in Balb/c mice model of breast cancer

“…Similar to many cancers, multiple triggering causative agents are considered to play a role in BC development from advanced age and intrinsic predisposing parameters to environmental triggers. Drug resistance is a rising issue in BC and is a main cause of patient death 6,7 . Surgery and radiotherapy that are used to eradicate localized tumours are ineffective in preventing metastases 8,9 .…”

“…Drug resistance is a rising issue in BC and is a main cause of patient death. 6 , 7 Surgery and radiotherapy that are used to eradicate localized tumours are ineffective in preventing metastases. 8 , 9 Although chemotherapy is one of the most usual therapeutic methods, due to the lack of selective cytotoxicity, this treatment is associated with many side effects.…”