Tyrosine kinase signalling within cancer cells is central to the establishment of an immunosuppressive microenvironment. Although tyrosine kinase inhibitors act, in part, to augment adaptive immunity, the increased heterogeneity and functional redundancy of the tyrosine kinome is a hurdle to achieving durable responses to immunotherapies. We previously identified the Shc1 (ShcA) scaffold, a central regulator of tyrosine kinase signalling, as essential for promoting breast cancer immune suppression. Herein we show that the ShcA pathway simultaneously activates STAT3 immunosuppressive signals and impairs STAT1-driven immune surveillance in breast cancer cells. Impaired Y239/Y240-ShcA phosphorylation selectively reduces STAT3 activation in breast tumours, profoundly sensitizing them to immune checkpoint inhibitors and tumour vaccines. Finally, the ability of diminished tyrosine kinase signalling to initiate STAT1-driven immune surveillance can be overcome by compensatory STAT3 hyperactivation in breast tumours. Our data indicate that inhibition of pY239/240-ShcA-dependent STAT3 signalling may represent an attractive therapeutic strategy to sensitize breast tumours to multiple immunotherapies.
Aim: To describe the direct healthcare costs associated with repeated cytotoxic chemotherapy treatments for recurrent high-grade serous cancer (HGSC) of the ovaries. Patients & methods: Retrospective review of 66 women with recurrent stage III/IV HGSC ovarian cancer treated with repeated lines of cytotoxic chemotherapy in a Canadian University Tertiary Center. Results: Mean cost of treatment of first relapse was CAD$52,227 increasing by 38% for two, and 86% for three or more relapses with median overall survival of 36.0, 50.7 and 42.8 months, respectively. In-hospital care accounted for 71% and chemotherapy drugs accounted for 17% of the total costs. Conclusion: After the third relapse of HGSC, cytotoxic chemotherapy did not prolong survival but was associated with substantially increased healthcare costs.
Background: Depending on their path of differentiation, immune cells can have opposing roles in tumour progression. As a result, during growth, tumours undergo selective pressure to produce immunosuppressive factors that contribute to tumour growth, angiogenesis, and metastasis. This review discusses the contribution of different macrophages and T cells to tumour progression, as well as their role in current cancer immunotherapies.
Methods: We searched for articles online through McGill Library with search terms including the names of different immune cells along with “polarity”, “tumour progression”, or “cancer immunotherapy”. Cancer therapies “CTLA-4 blockade”, “Ipilimumab”, “adoptive cell transfer”, and “PD1 inhibition” were also used as search terms.
Summary: Depending on the cell types involved, crosstalk between different immune cells in the tumour stroma can contribute to either the development or the inhibition of tumour growth. Certain therapies such as adoptive cytotoxic T lymphocyte (CTLs) transfer and CTLA-4 & PD1 inhibition work by enhancing CTL tumoricidal responses, and have produced durable responses in a small but significant group of patients. Other therapies work by skewing the phenotype of tumour associated macrophages from pro-tumorigenic to anti-tumorigenic. However, disrupting the balance between immune cell functions risks triggering inflammatory disorders such as autoimmunity. Therefore, future directions in cancer immunotherapy include targeting potential responders and restricting therapeutic mechanisms to the tumour microenvironment.
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