Abstract SP090: Tumor INF signaling - A double edged sword in cancer

Abstract

Abstract Our pre-clinical research using breast cancer models has revealed how certain inflammatory pathways can have opposing effects on primary disease and metastasis. We also learned that immunological age can impact response to therapy, leading to age-stratified outcomes. In one study, we developed pre-clinical models of triple-negative breast cancer (TNBC) lung metastasis. We uncovered mechanisms by which certain primary breast cancers can prevent their disseminated tumor cells from generating tumors. These primary tumors elicit a systemic innate immune response involving IL-1β-expressing neutrophils that infiltrate the lungs. Our group and others had previously established that IL-1β promotes primary breast cancer growth. However, we found that in the lungs, IL-1β maintains disseminated tumor cells in an undifferentiated, non-proliferative state. Inhibiting either inflammation or IL-1R signaling enables robust outgrowth of lung metastases. Importantly, we found that among patients with lymph node-positive breast cancer (i.e., those at high risk for metastasis) high IL-1β associates with improved overall survival and distant metastasis-free survival. Our findings reveal a double-edged sword in which IL-1R inhibitors might reduce primary disease but promote metastatic disease. To avoid this dichotomy, we are exploring strategies that prevent disseminated tumor cell differentiation, as was achieved here by IL-1β, to prevent metastatic outgrowth and provide a window of opportunity to target early metastases. As another example, we evaluated immune checkpoint blockade (ICB) therapy using various pre-clinical TNBC models in young and aged mice. We observed reduced tumor growth and improved survival in response to anti-PD-1 and anti-CTLA-4 treatment in young mice compared to aged mice. Immune profiling of peripheral blood and tumor samples demonstrated differences between young and aged mice treated with immune checkpoint blockade. To gain insights into the mechanisms behind those results, we performed whole tumor RNAseq on treated young versus aged mice. Notably, the most significantly enriched gene signatures included genes in interferon response pathways - with impaired responses in tumors of aged mice. Informed by those findings, we interrogated the METABRIC tumor gene expression database, stratifying TNBC patients < 40 and > 65 years of age. Two distinct clusters were identified, including enrichment of interferon-related genes in the "young" cohort. Turning back to our pre-clinical models, we used a drug that stimulates interferon response genes (STING agonists) in combination with ICB and found significantly improved survival in the aged cohorts. Our study demonstrated that age determines the T cell inflamed phenotype and affects response to immune checkpoint blockade in TNBC. Evaluating interferon-related genes from tumor genomic data may aid identification of patients for whom combination therapy including an interferon pathway activator with ICB may be required. These findings highlight the need to understand how inflammatory signatures should be interpreted in order to design more effective clinical phase trials and how pre-clinical models need to better mimic intent-to-treat populations. Citation Format: SS McAllister. Tumor INF signaling - A double edged sword in cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP090.