Targeting tumor-associated myeloid cells: the new grail in immuno-oncology?
Strategies to target tumor-associated myeloid cells
Different strategies are explored in targeting tumor-associated myeloid cells.2 One is to deplete these cells or inhibit their infiltration in the tumors. An explored approach for this strategy is to shut down the signals attracting MDSCs to the tumors—in other words, chemokine blockade. Different compounds have been tested to target CCR5 and CXCR2 receptors, showing promising results in preclinical settings, and are currently in clinical trials.3 Another strategy is to induce differentiation and/or maturation of these cells, i.e., reprogram them toward an anti-tumor function. For example, TAMs are heterogeneous but considered M2-like macrophages, meaning with a pro-tumorigenic profile. Compounds are now designed to reprogram them toward an anti-tumor M1-like profile. One of the targets studied for this strategy is the T-like receptors family. These proteins, highly expressed on innate immune cells, are known to detect microbes and trigger an inflammatory immune response through activation of these cells. An historically known activator of TLRs, bacillus Calmette-Guérin (BCG) was “repurposed” from a tuberculosis vaccine to a bladder cancer treatment in the 1970s, and is still used today in combination with anti-PD-1 therapy, although its precise mechanism of action remains unclear.4 Different TLR-targeting compounds have been investigated as potential trigger to reprogram TAMs, but to date, Imiquimod is the only TLR agonist to be approved by the FDA for the treatment of squamous and basal cell carcinomas.2
As mentioned, tumor-associated myeloid cells are receiving a lot of attention these past few years, and rightly so as targets for not just novel therapies but as a tool for clinical prognosis. These cells are highly heterogeneous and complex, and they interact with virtually all other cellular components of the TME. Therefore, a better understanding of the myeloid landscape in tumors will help develop novel, or improve existing, treatments. As such, relevant physiological preclinical models for their study are of paramount importance.
- Schoenfeld AJ, Hellmann MD. Acquired Resistance to Immune Checkpoint Inhibitors. Cancer Cell. 2020 Apr 13;37(4):443-455.
- Mantovani A, Marchesi F, Jaillon S, Garlanda C, Allavena P. Tumor-associated myeloid cells: diversity and therapeutic targeting. Cell Mol Immunol. 2021 Mar;18(3):566-578.
- Law AMK, Valdes-Mora F, Gallego-Ortega D. Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer. Cells. 2020 Feb 27;9(3):561.
- Pettenati C, Ingersoll MA. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat Rev Urol. 2018 Oct;15(10):615-625.