Effectively harnessing the power of the immune system is one of the most promising advances in cancer therapy. Immune-based therapies take advantage of the tumor killing capacity of cytotoxic T cells, an ability that is normally limited within tumors via multiple suppressive pathways. Supporting the activity of these cytotoxic T cells can provide long-term survival advantages, but despite recent successes, only a fraction of patients respond to immunotherapy, and efficacious treatment has so far been largely limited to select tumor types. The identification of additional therapeutic targets is urgently needed to address these issues and expand upon the number of patients who will benefit from this relatively safe and effective treatment approach.
The Ruffell Lab is focused on understanding the role of key myeloid subsets within hormone-drive malignancies in order to identify and develop novel therapeutic targets and approaches. These include:
Dendritic cells are a rare population of immune cell that are responsible for controlling when, where, and how the immune system responds to infection and insult, essentially acting as ‘generals’ of the immune system. We have recently found that dendritic cells are also critical in supporting cytotoxic T cell activity within breast tumors following chemotherapy, and expression of dendritic cell genes can predict response to chemotherapy as well as long-term survival. We therefore hypothesize that dendritic cells have an unappreciated role in providing ‘logistical support’ to cytotoxic T cells within tumors. By evaluating therapeutic targeting of putative activating and inhibitory pathways on dendritic cells we seek to enhance their capacity to support cytotoxic T activity within breast tumors to improve response rates to both traditional and emerging therapeutics.
Ruffell B, Strachan DC, Chan V, Rosenbusch A, Ho CMT, Pryer N, Daniel D, Rugo HS, Coussens LM. (2014) Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26 (5): 623-637. PMCID 4254570
Gardner A, Ruffell B. (2016) Dendritic cells and cancer immunity. Trends Immunol. 37 (12): 855-865. PMCID 51355568
de Mingo Pulido A, Gardner A, Hiebler S, Soliman H, Rugo HS, Krummel MF, Coussens LM, Ruffell B. (2018) TIM-3 regulates CD103+ dendritic cell function and response to chemotherapy in breast cancer. Cancer Cell 33 (1): 60-74.
Macrophages are present in all mammalian tissues, represented by unique phenotypic and functional resident populations that are critical for tissue development and homeostasis. Under non-pathological conditions, resident macrophages in many tissues originate from embryonic progenitors and are conserved through local proliferation. Within tumors, macrophages also originate from circulating monocytes and are one of the most prominent populations of immune cells. Although macrophages were originally thought to be part of an anti-tumor response, animal studies and clinical correlations indicate that macrophages promote tumorigenesis under most conditions by promoting invasion, angiogenesis, and survival, while also directly and indirectly suppressing a cytotoxic T cell response. Exceptions to this are found in colorectal cancer and under select therapeutic conditions where the macrophage phenotype is more closely associated with classical activation. Otherwise, targeting macrophages for depletion or repolarization can enhance response to multiple therapeutic modalities.
Daldrup-Link HE, Golovko D, Ruffell B, DeNardo DG, Castaneda R, Ansari C, Rao J, Tikhomiron GA, Wendland M, Corot C, Coussens LM. (2011) MR Imaging of tumor associated macrophages with clinically-applicable iron oxide nanoparticles. Clin. Cancer Res. 17; 5695-5704. PMCID: 3166957
DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirstrom K, West BL, Coussens LM. (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1(1): 54-67. PMCID: 3203524
Ruffell B, Affara NI, Coussens LM. (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol. 33 (3); 119-126. PMCID: 3294003
Strachan DC, Ruffell B, Oei Y, Bissell M, Coussens LM, Pryer N, Daniel D. (2013) CSF1R inhibition delays tumor growth in cervical and mammary transgenic mouse models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration of CD8+ T cells. OncoImmunology 2 (12); e26968. PMCID: 3902121
Shiao SL, Ruffell B, DeNardo DG, Fujikawa KA, Faddegon BA, Underhill DM, Park CC, Coussens LM. (2015) TH2-polarized CD4+ T cells and macrophages limit the efficacy of radiation therapy. Cancer Immunol Res 3 (5): 518-523. PMCID 4420686
Ruffell B, Coussens LM. (2015) Macrophages and therapeutic resistance in cancer. Cancer Cell 27 (4): 462-472. PMCID: 4400235
Juric V, Ruffell B, Evason KJ, Che L, Hu J, Chen X, Bishop JM. (2015) Monocyte-dependent liver injury promotes carcinogenesis in an oncogene-specific manner. J Hepatol. PMID: 26639397
Wolfe AR, Trenton NJ, Debeb BG, Larson R, Ruffell B, Chu K, Hittelman W, Diehl M, Reuben JM, Ueno NT, Woodward WA. (2016) Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models. Oncotarget 7 (50): 82482-82492. PMCID 5347707