STAT3 Activity Promotes Programmed-Death Ligand 1 Expression and Suppresses Immune Responses in Breast Cancer

Breast cancer is one of the major causes of mortality in women worldwide. The most aggressive breast cancer subtypes are human epidermal growth factor receptor-positive (HER2+) and triple-negative breast cancers. Therapies targeting HER2 receptors have significantly improved HER2+ breast cancer patient outcomes. However, several recent studies have pointed out the deficiency of existing treatment protocols in combatting disease relapse and improving response rates to treatment. Overriding the inherent actions of the immune system to detect and annihilate cancer via the immune checkpoint pathways is one of the important hallmarks of cancer. Thus, restoration of these pathways by various means of immunomodulation has shown beneficial effects in the management of various types of cancers, including breast. We herein review the recent progress in the management of HER2+ breast cancer via HER2-targeted therapies, and its association with the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) axis. In order to link research in the areas of medicine and mathematics and point out specific opportunities for providing efficient theoretical analysis related to HER2+ breast cancer management, we also review mathematical models pertaining to the dynamics of HER2+ breast cancer and immune checkpoint inhibitors.

Section: Pd-1/pd-l1 and Her2 Crosstalk In Breast Cancermentioning

confidence: 99%

Section: Pd-1/pd-l1 and Her2 Crosstalk In Breast Cancermentioning

confidence: 99%

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

Padmanabhan

Kheraldine

Meskin

et al. 2020

“…On another note, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) are crucial oncogenic pathways that regulate PD-L1 expression [30]. Transcriptional PD-L1 is not only regulated by the PI3K pathway [31], but also regulated by signal transducer and activator of transcription 3 (STAT3) [32], nuclear factor kappa B (NF-κB) [33], and B-cell CLL/lymphoma 3 (Bcl3) proto-oncogene [34]. Herein, we illustrated that the P-AKT/P-mTOR/P-70s6K pathway is a prime signaling pathway that is negatively influenced by Salmonella treatment in a tumor mice model while the MAPK pathway needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

Chen

Pangilinan

Lee

2019

Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.

“…Additionally, similar to humans, dogs with advanced cancer exhibit intrinsic T-cell defects as well as T-cell exhaustion [80]. Immune cell interplay with cancer cells is a JAK-STAT3/5 affair, as detailed in the special issue in several articles [24,25,81]. Like all other model systems, companion animals have strengths as well as weaknesses, both practically and conceptually.…”

Section: Advantages and Disadvantages Of Canine Tumor Modelsmentioning

confidence: 99%

Companion Animals as Models for Inhibition of STAT3 and STAT5

Kieslinger

Swoboda

Kramer

et al. 2019

The use of transgenic mouse models has revolutionized the study of many human diseases. However, murine models are limited in their representation of spontaneously arising tumors and often lack key clinical signs and pathological changes. Thus, a closer representation of complex human diseases is of high therapeutic relevance. Given the high failure rate of drugs at the clinical trial phase (i.e., around 90%), there is a critical need for additional clinically relevant animal models. Companion animals like cats and dogs display chronic inflammatory or neoplastic diseases that closely resemble the human counterpart. Cat and dog patients can also be treated with clinically approved inhibitors or, if ethics and drug safety studies allow, pilot studies can be conducted using, e.g., inhibitors of the evolutionary conserved JAK-STAT pathway. The incidence by which different types of cancers occur in companion animals as well as mechanisms of disease are unique between humans and companion animals, where one can learn from each other. Taking advantage of this situation, existing inhibitors of known oncogenic STAT3/5 or JAK kinase signaling pathways can be studied in the context of rare human diseases, benefitting both, the development of drugs for human use and their application in veterinary medicine.