Immune Checkpoint Inhibitors in Triple Negative Breast Cancer Treatment: Promising Future Prospects

Abstract

Immunotherapy has emerged as the fifth pillar of cancer treatment alongside surgery, radiotherapy, chemotherapy, and targeted therapy. Immune checkpoint inhibitors are the current superheroes of immunotherapy, unleashing a patient’s own immune cells to kill tumors and revolutionizing cancer treatment in a variety of cancers. Although breast cancer was historically believed to be immunologically silent, treatment with immune checkpoint inhibitors has been shown to induce modest responses in metastatic breast cancer. Given the inherent heterogeneity of breast tumors, this raised the question whether certain breast tumors might benefit more from immune-based interventions and which cancer cell-intrinsic and/or microenvironmental factors define the likelihood of inducing a potent and durable anti-tumor immune response. In this review, we will focus on triple negative breast cancer as immunogenic breast cancer subtype, and specifically discuss the relevance of tumor mutational burden, the plethora and diversity of tumor infiltrating immune cells in addition to the immunoscore, the presence of immune checkpoint expression, and the microbiome in defining immune checkpoint blockade response. We will highlight the current immune checkpoint inhibitor treatment options, either as monotherapy or in combination with standard-of-care treatment modalities such as chemotherapy and targeted therapy. In addition, we will look into the potential of immunotherapy-based combination strategies using immune checkpoint inhibitors to enhance both innate and adaptive immune responses, or to establish a more immune favorable environment for cancer vaccines. Finally, the review will address the need for unambiguous predictive biomarkers as one of the main challenges of immune checkpoint blockade. To conclude, the potential of immune checkpoint blockade for triple negative breast cancer treatment could be enhanced by exploration of aforementioned factors and treatment strategies thereby providing promising future prospects.

Evaluation of tumor immune contexture among intrinsic molecular subtypes helps to predict outcome in early breast cancer

“…19 These results raised the question whether certain breast tumors might benefit more from immune-based interventions and which cancer cell-intrinsic and/or microenvironmental factors define anti-tumor immune response. 20 However, it must be noted that all these pioneering studies suffered from technical limitations, only evaluating the global pool of TILs (commonly detected in H&E on stained histological slides via light microscopy), or only one or two particular subtypes of immune cells, detected by specific staining in immunohistochemistry. For instance, with their role as final effectors of immune response, a favorable impact of breast tumor-infiltrating CD8+ T cells on survival has been largely reported.…”

“… 19 These results raised the question whether certain breast tumors might benefit more from immune-based interventions and which cancer cell-intrinsic and/or microenvironmental factors define anti-tumor immune response. 20 …”

Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies

“…Success of immunotherapy in general, depends on the inherent immunogenicity of the tumor. Although, traditionally perceived as an immunologically “cold” type, BC, especially the TNBC subtype, is now being considered curable by immunotherapies ( 21 ). In this regard, the immune checkpoint inhibitors (ICI) targeting the negative regulators of T cell activation (cytotoxic T lymphocyte-associated protein-4/CTLA-4, programmed cell death protein-1/PD-1, and programmed death-ligand 1/PD-L1), have gained the most attention.…”

“…Immune checkpoint inhibitor (ICI) and DNA damage-response (DDR)-directed regimens are two fairly recent FDA-approved treatment options available for TNBC ( 21 , 22 ), benefitting only a very small number of patients ( 21 , 23 ). Interestingly, similar to chemotherapies, efficacies of both strategies are impacted by TIS ( 23 – 26 ).…”

Quantitative proteomics characterization of cancer biomarkers and treatment

“… 48 Furthermore, the sub-network identified through quantitative phosphoproteomics was highly correlated with clinically identified breast cancer subtypes. 49 , 50 , 51 SWATH/DIA-MS (state-of-the-art sequential windowed acquisition of all theoretical fragment ion/data-independent acquisition mass spectrometry) presented a promising complement for the stable classification of ovarian cancer subtypes. 52 , 53 Quantitative proteomics of reverse-phase protein array (RPPA) could be used to classify diffuse large B cell lymphoma.…”