With the major development of immunotherapies, evaluation of the immune response associated to cancer has become the new challenge for pathologists. In breast cancer, this perspective has been notably anticipated by the recent publication, in 2014, of international guidelines for assessment of tumor-infiltrating lymphocytes (TILs), on routine haematoxylin-eosin stains. This technical article aims at reviewing the main key points and different steps in evaluation of tumor-infiltrating lymphocytes, in order to allow an easy implementation of this putative biomarker in routine practice. Widespread diffusion of international guidelines is the key to development of a standardized and reproducible biomarker. This early learning phase is of particular importance, as immune response will probably play a major role as a prognostic and predictive biomarker, especially in triple-negative and HER2 positive breast cancer.

Immunotherapies targeting co-inhibitory receptors recently open a new promising approach of cancer treatment. Indeed, an objective clinical response was observed after treatment by anti-CTLA-4 and anti-PD-1 in many indications but the treatment still failed in 70 to 80 % of cases treated. Given the adverse effects and the high cost of these therapies, there is a need for the development of biomarkers. This review focus on potential predictive biomarkers. In peripheral blood, high level of Il-2 soluble receptor at baseline and absence of ICOS+ CD4-T lymphocytes induction may be associated with the absence of clinical response for melanoma patients treated by ipilimumab (anti-CTLA-4). PD-L1 - PD-1 ligand- expression on cancer lung adenocarcinoma and melanoma is associated with an improved clinical response to anti-PD-1/PD-L1. Nevertheless, a standardization of the biological assays is needed before a clinical translation. CD8-T cell tumor infiltration seems to be a prerequisite to an optimal clinical response after anti-PD-1/PD-L1 administration. In situ high mutational load is associated with a CD8-T cell infiltration and a higher rate of anti-PD-1 and anti-CTLA-4 response. If we consider a more holistic approach, the role of the gut microbiota in the response to these treatments is now well established in pre-clinical experiments. The universal marker is not identified so far, but the reliable marker should be in the tumor compartment and combining multiples markers could be suitable to predict response in different contexts.

The understanding of the biology of pancreatic carcinoma has greatly benefited from studies of genetic/epigenetic alterations and molecular expression in experimental models as well as precancerous and cancerous tissues by mean of molecular amplification and large-scale transcriptoma analysis. P16, TP53, DPC4/Smad4 tumor suppressor pathways are genetically inactivated in the majority of pancreatic carcinomas, whereas oncogenic k-ras is activated. The activating point mutation of the KRAS oncogene on codon 12 is the major event and occurs early in pancreatic carcinogenesis. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, Nerve Growth Factor, gastrin), of pro-angiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, tissue plasminogen activators) occurs. The microenvironment plays also a key role in the invasive and metastatic process of pancreatic carcinoma with a strong relationship between cancerous cells and pancreatic stellate cells as well as extracellular matrix. This microenvironment strongly participates to the tumor fibrosis, hypoxia and hypovascularization inducing an inaccessibility of drugs. Nowadays, the targeting of microenvironment takes a special place in the new therapeutic strategies of pancreatic cancer in combination with chemotherapy.

Despite the recent introduction of new drugs, castration-resistant metastatic prostate cancer, (mCRPC) remains a poor prognosis disease, with a crucial need for new therapeutic approaches. Tasquinimod is a newly developed molecule, orally administered, currently evaluated in phase III studies. Tasquinimod targets the tumor microenvironment, focusing on the angiogenic and immune components. Its specific action on the S100A9 protein restores immunity and reduces angiogenesis. A phase II double-blind randomized study against placebo showed an improvement of more than 50% of progression free survival in the group of mCRPC patients treated with tasquinimod, as compared to the placebo group. At a dose of 1mg/day, the tolerance of tasquinimod appeared acceptable. This review presents the available preclinical and clinical results of tasquinimod, with a particular focus on the originality of its mode of action.

The phosphoinositide-3 kinase (PI3K) - phosphoinositide-dependent protein kinase 1 (PDK1)-Akt/protein kinase B (PKB) cascade plays a critical role in cardiovascular development and tumor genesis. But the role of PDK1 in the microenvironment of heart and tumor remains unknown. To clarify the effects of PDK1 on tissue microenvironment in vivo, here, we created α-SMA-Cre-mediated excision of PDK1 mice. And the mice were injected subcutaneously with Lewis lung carcinoma (LLC) cells. We found PDK1-deficient mice had post-natal praecox dilated cardiomyopathy, decelerated tumor growth and severe tumor metastasis. Histopathological analysis revealed abnormality of vascular microenvironment in heart and primary tumor. In conclusion, PDK1 plays a pivotal role in regulating cardiac function and tumor metastasis by interfering with microenvironment.

BACKGROUND: Epithelial ovarian carcinoma (EOC) has a worst prognosis with little progress in terms of survival for the last two decades. Immunology received little interest in EOC in the past, but now appears very important in the natural history of this cancer. This review is an EOC immunology state of art and focuses on the place of immunotherapy in future.
METHODS: A systematic review of published studies was performed. Medline baseline interrogation was performed with the following keywords: \"Ovarian carinoma, immunotherapy, T-lymphocyte, regulator T-lymphocyte, dendritic cells, macrophage, antigen, chemotherapy, surgery, clinical trials\". Identified publications (English or French) were assessed for the understanding of EOC immunology and the place of conventional treatment and immunotherapy strategy.
RESULTS: Intratumoral infiltration by immune cells is a strong prognotic factor in EOC. Surgery and chemotherapy in EOC decrease imunosuppression in patients. The antitumoral immunity is a part of the therapeutic action of surgery and chemotherapy. Until now, immunotherapy gave some disappointing results, but the new drugs that target the tolerogenic tumoral microenvironnement rise and give a new hope in the treatment of cancer.
CONCLUSIONS: Immunology controls the EOC natural history. The modulation of immunosuppressive microenvironment associated with the stimulation of antitumoral immunity could be the next revolution in the treatment of cancer.