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<p>Calcium (Ca2+) is a known important second messenger. Calcium/Calmodulin (CaM) dependent protein kinase kinase 2 (CaMKK2) is a crucial kinase in the calcium signaling cascade. Activated by Ca2+/CaM, CaMKK2 can phosphorylate other CaM kinases and AMP-activated protein kinase (AMPK) to regulate cell differentiation, energy balance, metabolism and inflammation. Outside of the brain, CaMKK2 can only be detected in hematopoietic stem cells and progenitors, and in the subsets of mature myeloid cells. CaMKK2 has been noted to facilitate tumor cell proliferation in prostate cancer, breast cancer, and hepatic cancer. However, whethter CaMKK2 impacts the tumor microenvironment especially in hematopoietic malignancies remains unknown. Due to the relevance of myeloid cells in tumor growth, we hypothesized that CaMKK2 has a critical role in the tumor microenvironment, and tested this hyopothesis in murine models of hematological and solid cancer malignancies. </p><p>We found that CaMKK2 ablation in the host suppressed the growth of E.G7 murine lymphoma, Vk*Myc myeloma and E0771 mammary cancer. The selective ablation of CaMKK2 in myeloid cells was sufficient to restrain tumor growth, of which could be reversed by CD8 cell depletion. In the lymphoma microenvironment, ablating CaMKK2 generated less myeloid-derived suppressor cells (MDSCs) in vitro and in vivo. Mechanistically, CaMKK2 deficient dendritic cells showed higher Major Histocompatibility Class II (MHC II) and costimulatory factor expression, higher chemokine and IL-12 secretion when stimulated by LPS, and have higher potent in stimulating T-cell activation. AMPK, an anti-inflammatory kinase, was found as the relevant downstream target of CaMKK2 in dendritic cells. Treatment with CaMKK2 selective inhibitor STO-609 efficiently suppressed E.G7 and E0771 tumor growth, and reshaped the tumor microenvironment by attracting more immunogenic myeloid cells and infiltrated T cells.</p><p>In conclusion, we demonstrate that CaMKK2 expressed in myeloid cells is an important checkpoint in tumor microenvironment. Ablating CaMKK2 suppresses lymphoma growth by promoting myeloid cells development thereby decreasing MDSCs while enhancing the anti-tumor immune response. CaMKK2 inhibition is an innovative strategy for cancer therapy through reprogramming the tumor microenvironment.</p> / Dissertation

Les usages politiques du passé de la Résistance sont au cœur de cette thèse. Cette recherche n’entend donc pas se centrer sur la Résistance au sens strict, mais sur les formes d’instrumentalisation de ce passé, au sein d’un groupe : le Parti Communiste Français. Parmi les passés choisis par le PCF, la Résistance occupe une place déterminante, en raison du réel engagement communiste dans l’armée des ombres, ainsi qu’en raison du brevet de patriotisme qu’elle offrait à une formation créditée d’une fidélité aveugle à Moscou. La participation des communistes à l’épopée résistante leur a permis de reconquérir de la crédibilité et de consolider leur position dans un espace public où ils risquaient d’être disqualifiés en raison des positions adoptées par le parti en 1939-1941. La pluralité des significations attachées à ce passé et la fluidité des interprétations attribuées ont permis l’adaptation à la réalité dans laquelle agissaient les communistes. Ainsi, il a été possible de répondre aux objectifs divers que s’assignait le PCF. La période étudiée s’ouvre en 1944, avec la libération d’une grande partie du territoire français, même si la guerre n’est alors pas finie. L’étude s’achève avec l’année 1974, date significative que signale le XXXème anniversaire de la Libération dans le contexte national de la fin des Trente Glorieuses. / The political exploitation of its involvement in the resistance movement is the subject of this thesis. The objective of this study is not the Resistance per se but how it was used for political purposes by the French Communist Party. The Resistance is an essential period for the FCP not only because of its real involvement in the Resistance movement but also because this involvement was used to hide its blind alliance to Moscow. The involvement of the FCP in the Resistance allowed it to regain credibility and to strengthen its position in despite the errors committed between 1939 and 1941. The multiple interpretations and exploitations of its involvement in the Resistance were adapted by the party according to its political objectives and needs in any given moment. The historical period of this research begin in 1944 with the Liberation and ends in 1974, the 30th Anniversary of this date.