Immunosuppressive Myeloid Cells

Overview of IMCs

In the intricate landscape of cancer, two distinct hallmarks stand out prominently: the promotion of tumor-inducing inflammation and the cunning evasion of immune destruction. Within this context, innate immune cells, among which neutrophils, monocytes, and macrophages take center stage, serve as pivotal mediators, orchestrating both sterile and nonsterile inflammatory responses. However, the sustained and relentless inflammation witnessed in cancer poses a significant disruption to the normal process of myelopoiesis. This disruption sets in motion a cascade of events, culminating in the emergence of immunosuppressive myeloid cells (IMCs), notably the myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). These myeloid entities, endowed with potent immunosuppressive capabilities against effector lymphocytes, become highly abundant denizens of the tumor microenvironment, effectively erecting a formidable barrier against the potential success of cancer immunotherapy endeavors.

Fig. 1 The connection between cancer-associated inflammation and myeloid-mediated immunosuppression.¹

Creative Biolabs is actively engaged in a multifaceted exploration of therapeutic avenues aimed squarely at combatting these IMCs. This concerted effort spans a spectrum of strategies, encompassing the deployment of anti-inflammatory agents, the deliberate obstruction of myeloid cell mobilization and survival, and the judicious application of immunostimulatory adjuvants. In a recent and promising development, the spotlight has shifted towards immune checkpoint molecules expressed on the surface of tumor-infiltrating myeloid cells. These molecules have emerged as tantalizing therapeutic targets, potentially capable of redirecting these cells toward a mission to eliminate cancerous cells within the tumor milieu. The pursuit of these innovative therapeutic approaches represents a dynamic frontier in the ongoing battle against cancer.

Case Study

Enhancing colorectal cancer immunotherapy through reprogramming of IMCs. (Lu, et al., 2021)

Fig. 2 Enhancing colorectal cancer immunotherapy through reprogramming of IMCs.²
In the context of colorectal cancer, where immune checkpoint blockade (ICB) exhibits limited efficacy, the imperative to concurrently target complementary mechanisms becomes evident. Our investigation has pinpointed prostaglandin E2 (PGE2) receptor 4 (EP4) as the central orchestrator governing the activities of IMCs, which stand as the primary culprits behind resistance to ICB therapy. To unravel the immunotherapeutic potential inherent in EP4 signaling, we have engineered a novel, highly selective EP4 antagonist capable of effectively incapacitating IMC function. In vivo experiments validate its ability to augment cytotoxic T-cell-mediated tumor eradication. In summary, this research underscores the promise of inhibiting EP4-expressing IMCs as a prospective strategy to enhance the effectiveness of immunotherapy in the context of colorectal cancer.

Approaches to targeting MDSCs. (De Cicco, et al., 2020)

Fig. 3 Approaches to targeting MDSCs.³
Research conducted in murine models has elucidated that MDSCs amass within various cancer types, facilitating invasion, angiogenesis, and the formation of metastases while concurrently suppressing antitumor immune responses. Consequently, MDSCs pose a significant impediment to numerous cancer immunotherapies, making their targeted depletion an auspicious strategy for enhancing the efficacy of immunotherapeutic interventions. In this comprehensive review, the authors provide a summation of the phenotypic characteristics and the mechanisms underlying the suppressive functions of MDSC populations expanded within distinct tumor microenvironments, highlighting their clinical significance in the realms of cancer diagnosis and therapy.

Services in Creative Biolabs

Creative Biolabs offers an extensive array of customized services pertaining to immune checkpoints, including but not limited to Biomarker Development for Immune Checkpoint Inhibitor (ICI), Immune Checkpoint Assays, and Preclinical Research for Immune Checkpoint Targeting Drugs, among others. For additional information, please do not hesitate to get in touch with us.

References

Nakamura, et al. "Myeloid immunosuppression and immune checkpoints in the tumor microenvironment." Cellular & molecular immunology 17.1 (2020): 1-12.
Lu, Weiqiang, et al. "Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer." EMBO molecular medicine 13.1 (2021): e12798.
De Cicco, et al. "The new era of cancer immunotherapy: targeting myeloid-derived suppressor cells to overcome immune evasion." Frontiers in immunology 11 (2020): 550783.

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