Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy

Abstract

Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors.

Integrative Radiogenomics Approach for Risk Assessment of Post-Operative Metastasis in Pathological T1 Renal Cell Carcinoma: A Pilot Retrospective Cohort Study

“…Macrophages are the most abundant subpopulations of tumor-infiltrating immune cells, and high M0 and M2 macrophage fractions were related to a poor outcome, which might reflect their gradual change in function in RCC [52,53]. The tumor-promoting effects of EMT shift to M1 type, which are considered to exert anticancer effects via cytotoxicity and immune rejection to M2, similar to tumor-associated macrophages that are considered to promote cancer growth via EMT, angiogenesis, and immunosuppression [52,56]. Tregs combined with CTLA4, LAG3, and TIGIT related to a worse prognosis in RCC exerted immunosuppressive effects, favoring tumor escape from the activity of a variety of antitumor immune effector cells [52,53].…”

KISS1/KISS1R and Breast Cancer: Metastasis Promoter

“…52,53 However, clinical trial results indicate lower-than-expected impact on survival with checkpoint inhibitors in the metastatic setting and thus combination therapies with targets directed at EMT-related pathways are being explored. 54 Additionally, TNBC tumors exhibit extensive epigenetic alterations via DNA methylation and novel drug targets aimed at epigenetic re-programming such as BET bromo-domain inhibitors alone or in combination with immunotherapy are targeted for hypermethylated tumors and are also in clinical trials. 5,55 Molecular pathways that modulate tumorigenesis are deregulated in the aggressive TNBC phenotype.…”

Immune checkpoint blockade therapies for HCC: current status and future implications

“…EMT facilitates immune evasion of tumor cells by influencing these immunosuppressive TME cells. For instance, EMT promotes an immunosuppressive TME by recruitment of tumor-associated macrophages through regulation of cytokines [95] . EMT also contributes to immunosuppression through regulation of immune checkpoint molecules as reported in several instances earlier in this review.…”