Prognostic impact of circulating Her-2-reactive T-cells producing pro- and/or anti-inflammatory cytokines in elderly breast cancer patients

Clinico-pathological characteristics of younger and older patients. (DOCX 15 kb

Checkpoint Inhibition in Myeloma: Opportunities and Challenges

Despite major improvements in the treatment landscape, most multiple myeloma (MM) patients eventually succumb to the underlying malignancy. Immunotherapy represents an attractive strategy to achieve durable remissions due to its specificity and capacity for long term memory. Activation of immune cells is controlled by a balance of agonistic and inhibitory signals via surface and intracellular receptors. Blockade of such inhibitory immune receptors (termed as “immune checkpoints”) including PD-1/PD-L1 has led to impressive tumor regressions in several cancers. Preclinical studies suggest that these immune checkpoints may also play a role in regulating tumor immunity in MM. Indeed, myeloma was among the first tumors wherein therapeutic efficacy of blockade of PD-1 axis was demonstrated in preclinical models. Expression of PD-L1 on tumor and immune cells also correlates with the risk of malignant transformation. However, early clinical studies of single agent PD-1 blockade have not led to meaningful tumor regressions. Immune modulatory drugs (IMiDs) are now the mainstay of most MM therapies. Interestingly, the mechanism of immune activation by IMiDs also involves release of inhibitory checkpoints, such as Ikaros-mediated suppression of IL-2. Combination of PD-1 targeted agents with IMiDs led to promising clinical activity, including objective responses in some patients refractory to IMiD therapy. However, some of these studies were transiently halted in 2017 due to concern for a possible safety signal with IMiD-PD1 combination. The capacity of the immune system to control MM has been further reinforced by recent success of adoptive cell therapies, such as T cells redirected by chimeric-antigen receptors (CAR-Ts). There remains an unmet need to better understand the immunologic effects of checkpoint blockade, delineate mechanisms of resistance to these therapies and identify optimal combination of agonistic signaling, checkpoint inhibitors as well as other therapies including CAR-Ts, to realize the potential of the immune system to control and prevent MM

Prognostic impact of high levels of circulating plasmacytoid dendritic cells in breast cancer

Additional file 2: Table S1. Patients clinico-pathological parameters

Prognostic impact of high levels of circulating plasmacytoid dendritic cells in breast cancer

Abstract Background Identifying immune markers in blood that are informative for breast cancer patient survival would not only be useful for prognosis but might also provide mechanistic insights into processes facilitating survival. Methods We phenotyped circulating plasmacytoid dendritic cells (pDCs), myeloid-derived suppressor cells (MDSCs) and regulatory T-cells in relation to T-cell responses to Her-2 in vitro in 75 untreated breast cancer patients 28–87 years of age at diagnosis. Results Patients with later stage tumors had lower levels of circulating pDCs (p = 0.008). There was a positive association between 5-year survival and higher than median levels of circulating pDCs (p = 0.03). We confirmed that 5-year survival correlated with CD8+ but not CD4+ T-cell responsiveness to Her-2 peptides in this cohort of younger and older patients (p = 0.04). Including pDCs in the analysis of previously-established parameters revealed that patients who had a CD8+ T-cell response to Her-2 together with a low ratio of MDSCs:pDCs had 100 % 5-year survival. High levels of pDCs and the presence of a CD8+ T-cell response to Her-2 were independent positive survival indicators according to multivariate Cox analysis. Conclusions Our new results suggest that circulating pDCs could be a positive prognostic indicator in breast cancer patients of all ages, together with the previously established CD8+ T-cell reactivity to Her-2 antigens in older patients only. These two prognostic indicators were independent and emphasize the important role of immunity in ensuring breast cancer patient survival, even in those not undergoing immunotherapy

Immune profiles of elderly breast cancer patients are altered by chemotherapy and relate to clinical frailty

Effective therapeutic management of elderly patients with cancer, on an individual basis, remains a clinical challenge. Here, we identify novel biomarkers to assess elderly patients (≥70 years of age) with breast cancer undergoing treatment with or without chemotherapy.status: publishe

Low levels of intra-tumoural T cells in breast cancer identify clinically frail patients with shorter disease-specific survival

OBJECTIVES: The global health status of older patients with cancer influences their clinical course, but little is known regarding the influence of the immune system on the global health of older patients with cancer. The goal of this study was to assess the relationships between patient fitness/frailty status and survival, and the local tumour immune environment of older patients with breast cancer. MATERIALS AND METHODS: In a cohort of 58 older patients with breast cancer (over 70 years of age), fluorescence microscopy was used to investigate whether levels of intra-tumoural T cells (CD3+) and granulocytic cells (CD15+) could predict clinical outcome, and/or whether they correlated with patient physical and mental performance as evaluated by comprehensive geriatric assessment. RESULTS: We observed that patients with higher levels of intra-tumoural T cells were fitter according to a number of clinical health measures including G8 (p = 0.006), Karnofsky Index (p = 0.0372), and Leuven Oncology Frailty Score (LOFS) (p = 0.0187). In contrast, high relative levels of granulocytic cells were found in patients with poorer clinical health (LOFS, p = 0.0474). Furthermore, high levels of T cells but not granulocytic cells were associated with longer breast cancer-specific survival (p = 0.0444). CONCLUSIONS: This is the first study to show that low relative levels of intra-tumoural T cells are associated with inferior patient fitness. In contrast to T cells, we observed that intra-tumoural granulocytic cells displayed an inverse relationship with patient performance. Further research is needed to determine whether boosting the level of intra-tumoural T cells in older non-fit patients can result in improved outcome.status: publishe