Marie Laure Poillot

Bio: Marie Laure Poillot is an academic researcher. The author has contributed to research in topics: Cytotoxic T cell & CD8. The author has an hindex of 2, co-authored 2 publications receiving 156 citations.

The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer.

Abstract: Several cell-intrinsic alterations have poor prognostic features in human breast cancer, as exemplified by the absence of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-positive puncta in the cytoplasm (which indicates reduced autophagic flux) or the loss of nuclear HMGB1 expression by malignant cells. It is well established that breast cancer is under strong immunosurveillance, as reflected by the fact that scarce infiltration of the malignant lesion by CD8(+) cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3(+) regulatory T cells or CD68(+) tumor-associated macrophages), resulting in low CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios, has a negative prognostic impact. Here, we reveal the surprising finding that cell-intrinsic features may influence the composition of the immune infiltrate in human breast cancer. Thus, the absence of LC3B puncta is correlated with intratumoral (but not peritumoral) infiltration by fewer CD8(+) cells and more FOXP3(+) or CD68(+) cells, resulting in a major drop in the CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3(+) and CD68(+) cells, both within the tumor and close to it. Combined analysis of LC3B puncta and HMGB1 expression allowed for improved stratification of patients with respect to the characteristics of their immune infiltrate as well as overall and metastasis-free survival. It can be speculated that blocked autophagy in, or HMGB1 loss from, cancer cells may favor tumor progression due to their negative impact on anticancer immunosurveillance.

Combined evaluation of LC3B puncta and HMGB1 expression predicts residual risk of relapse after adjuvant chemotherapy in breast cancer.

Abstract: In spite of adjuvant chemotherapy, a significant fraction of patients with localized breast cancer (BC) relapse after optimal treatment. We determined the occurrence of cytoplasmic MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3B)-positive puncta, as well as the presence of nuclear HMGB1 (high mobility group box 1) in cancer cells within surgical BC specimens by immunohistochemistry, first in a test cohort (152 patients) and then in a validation cohort of localized BC patients who all received adjuvant anthracycline-based chemotherapy (1646 patients). Cytoplasmic LC3B(+) puncta inversely correlated with the intensity of SQSTM1 staining, suggesting that a high percentage cells of LC3B(+) puncta reflects increased autophagic flux. After setting optimal thresholds in the test cohort, cytoplasmic LC3B(+) puncta and nuclear HMGB1 were scored as positive in 27.2% and 28.6% of the tumors, respectively, in the validation cohort, while 8.7% were considered as double positive. LC3B(+) puncta or HMGB1 expression alone did not constitute independent prognostic factors for metastasis-free survival (MFS) in multivariate analyses. However, the combined positivity for LC3B(+) puncta and nuclear HMGB1 constituted an independent prognostic factor significantly associated with prolonged MFS (hazard ratio: 0.49 95% confidence interval [0.26-0.89]; P = 0.02), and improved breast cancer specific survival (hazard ratio: 0.21 95% confidence interval [0.05-0.85]; P = 0.029). Subgroup analyses revealed that within patients with poor-prognosis BC, HMGB1(+) LC3B(+) double-positive tumors had a better prognosis than BC that lacked one or both of these markers. Altogether, these results suggest that the combined positivity for LC3B(+) puncta and nuclear HMGB1 is a positive predictor for longer BC survival.

Immunogenic cell death in cancer and infectious disease

Abstract: Immunogenicity depends on two key factors: antigenicity and adjuvanticity. The presence of exogenous or mutated antigens explains why infected cells and malignant cells can initiate an adaptive immune response provided that the cells also emit adjuvant signals as a consequence of cellular stress and death. Several infectious pathogens have devised strategies to control cell death and limit the emission of danger signals from dying cells, thereby avoiding immune recognition. Similarly, cancer cells often escape immunosurveillance owing to defects in the molecular machinery that underlies the release of endogenous adjuvants. Here, we review current knowledge on the mechanisms that underlie the activation of immune responses against dying cells and their pathophysiological relevance.

Approaches to treat immune hot, altered and cold tumours with combination immunotherapies

Abstract: Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. It is increasingly clear that the effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Therefore, a general consensus emerged on the central part played by effector T cells in the antitumour responses. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy. In this Review, we focus on defining hot, altered and cold tumours, the complexity of the tumour microenvironment, the Immunoscore and immune contexture of tumours, and we describe approaches to treat such tumours with combination immunotherapies, including checkpoint inhibitors. In the upcoming era of combination immunotherapy, it is becoming critical to understand the mechanisms responsible for hot, altered or cold immune tumours in order to boost a weak antitumour immunity. The impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.

Targeting autophagy in cancer

Abstract: Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

The immune contexture in cancer prognosis and treatment

Abstract: Immunotherapy is currently the most rapidly advancing area of clinical oncology, and provides the unprecedented opportunity to effectively treat, and even cure, several previously untreatable malignancies. A growing awareness exists of the fact that the success of chemotherapy and radiotherapy, in which the patient's disease can be stabilized well beyond discontinuation of treatment (and occasionally is cured), also relies on the induction of a durable anticancer immune response. Indeed, the local immune infiltrate undergoes dynamic changes that accompany a shift from a pre-existing immune response to a therapy-induced immune response. As a result, the immune contexture, which is determined by the density, composition, functional state and organization of the leukocyte infiltrate of the tumour, can yield information that is relevant to prognosis, prediction of a treatment response and various other pharmacodynamic parameters. Several complementary technologies can be used to explore the immune contexture of tumours, and to derive biomarkers that could enable the adaptation of individual treatment approaches for each patient, as well as monitoring a response to anticancer therapies.