Identifying the role of interferon and interferon-regulated chemokines in stress-induced immunosuppression in triple negative breast cancer

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ABSTRACT In the United States, breast cancer is the most commonly diagnosed cancer and second leading cause of cancer- related deaths among women of all ages and racial/ethnic groups. Immune checkpoint inhibitors (ICIs) are currently being used for the treatment of triple negative breast cancer (TNBC), which comprises 15% of all breast cancer diagnoses, especially in younger women, and is the most aggressive and lethal subtype; however, only 5-20% of TNBC patients are responsive to current ICI monotherapy and new strategies are urgently needed to help others overcome treatment resistance. One mechanism of resistance to ICIs is lower expression levels of intratumoral chemokines CXCL9 and CXCL10 that are essential for attracting anti-tumor CD8+ T cells to the tumor microenvironment (TME). The proposed research will evaluate whether stress-induced molecular pathways are linked to the expression of these chemokines. Psychosocial stress is associated with both increased incidence and mortality of breast cancer according to epidemiological studies, and between 30-75% of breast cancer patients experience psychological stress, which can enhance β-adrenergic signaling, potentially reducing the efficacy of ICIs. However, the specific role of psychosocial stress in the development of treatment resistance to ICIs among TNBC patients remains unknown. Our team's research in preclinical mouse models has shown that chronic stress and its mediators, epinephrine (EPI) and norepinephrine (NE), drive immunosuppression in the TME by decreasing CD8+ T cells and increasing immunosuppressive cells, thus promoting tumor growth. Our subsequent study provided preliminary evidence that propranolol, a pan-β-blocker, improves responses to ICIs in patients with metastatic melanoma from 30-40% to 78%. We also found that chronic stress via EPI increases prostaglandin E2 (PGE2). Further, we and others have shown that PGE2 inhibits interferon (IFN)-induced CXCL9 and CXCL10 secretion. Thus, we hypothesize that chronic stress promotes immunosuppression in TNBC by increasing PGE2 and inhibiting IFN pathways, which ultimately leads to decreases in CXCL9 and CXCL10. We will test our hypothesis by correlating validated measures of psychosocial stress with levels of IFN, PGE2, CXCL9 and CXCL10, and immune cells in prospectively collected tumor tissues from breast cancer patients. The proposed study will (i) investigate a novel mechanistic pathway of stress-induced tumor progression and (ii) be the first to test if high levels of perceived stress are associated with immunosuppression in a study using human breast cancer samples. Completion of the proposed work is expected to provide crucial insights into the role of the PGE2-IFN-chemokine pathway in stress-induced immunosuppression in the TME, which will allow us to develop future competitive NIH grant proposals (e.g., R01) to obtain a comprehensive understanding of this pathway and its potential to be therapeutically targeted. This could eventually lead to improved clinical outcomes for not only patients with immunotherapy- resistant TNBC, but also other cancer patients affected by tumor immunosuppression.