_:b16832016 "The recent success of immunotherapy based on anti CTLA-4 antibodies inducing increased overall survival (OS)13 in advanced melanoma confirms the relevance of T cell based anti tumor immunity (for review, see ref. >>14<<) and suggests that education and activation of immune system could promote tumor control." . _:b16832046 . . _:b497088955 . _:b16832021 . _:b16832018 "The T-cell receptor (TCR) combinatorial diversity results from mechanisms by which exons encoding TCR variable regions are assembled in developing T lymphocytes from germline variable (V), diversity (D), and joining (J) gene segments.15,>>16<< Genomic V(D)J rearrangements leading to combinatorial diversity is of fundamental importance for the generation of diverse antigen receptor repertoires." . _:b16832032 . _:b16832039 . _:b16832008 "3 Importantly, in MBC patients lymphopenia in combination with PS > 1, is associated with a 20% risk of early death at 1\u00A0mo and 50% risk at 3\u00A0mo.3,>>5<<,6 In addition, lymphopenia is also associated with an increased risk of disease progression and worse long-term survival in three prospectively collected series of patients with MBC at first line, along with non-Hodgkin lymphoma, and soft" . . . _:b497089052 . . _:b16832012 . . . . . _:b16832027 . _:b497089007 . _:b16832007 "3 Importantly, in MBC patients lymphopenia in combination with PS > 1, is associated with a 20% risk of early death at 1\u00A0mo and 50% risk at 3\u00A0mo.>>3<<,5,6 In addition, lymphopenia is also associated with an increased risk of disease progression and worse long-term survival in three prospectively collected series of patients with MBC at first line, along with non-Hodgkin lymphoma, and" . _:b497088978 . _:b497089050 . . . _:b16832005 . _:b16832021 "20 In melanoma, a progressive widening of the repertoire diversity under chemo-immunotherapy treatment was accompanied by high avidity and tumor reactivity of Melan-A-specific T-cell clones.>>21<<" . _:b16832032 "Lymphocyte count and diversity are the two dimensions required for an efficient immune response.6,>>24<< While a minimum number of lymphocytes is required, TCR diversity could reflect the capacity to recognize an antigen." . _:b16832042 "As the study enrolled only previously untreated patients, lymphopenia or divpenia do not result from previous exposure to cytotoxic agents as described by others.>>30<<" . _:b16832041 . . _:b16832047 "Lymphopenia and divpenia may result not only from reduced thymic function but also from the destruction of lymphocytes elicited by breast tumor cells expressing pro-apoptotic ligands,>>34<< a blockade of lymphocyte proliferation via inhibitory molecules (PD-L1) expressed by tumor cells,35 or a reduced capacity of lymphocytes to respond to TCR stimulation due to an alteration of \u03B6 chain expression." . . . _:b497088945 . _:b497088984 . . . _:b497088994 . . . _:b497088995 . . _:b497089021 . _:b16832031 "Lymphocyte count and diversity are the two dimensions required for an efficient immune response.>>6<<,24 While a minimum number of lymphocytes is required, TCR diversity could reflect the capacity to recognize an antigen." . . _:b16832048 . . . . . . _:b497088990 . _:b497089004 . _:b497089051 . _:b16832006 . _:b16832007 . . _:b497089019 . _:b16832012 "7 However, tumors develop escape mechanisms including production of immunosuppressive cytokines, alteration of dendritic cell subsets differentiation or function,>>8<<-10 and recruitment of immunosuppressive regulatory T-cells (Treg)." . _:b497088982 . . _:b16832005 . . . _:b497089033 . _:b497088996 . _:b497088991 . _:b16832005 . . . _:b497089016 . _:b497089009 . . _:b16832038 "27 Such long lasting effects were also observed in lymphopenic cancer patients where T cell counts increased few weeks after the IL-7 cycle and remaind stable.>>6<<" . _:b16832023 "OS was defined as the time from patient\u2019s inclusion to the date of death or the date of the last follow-up for alive patients. Survival distributions were estimated by the Kaplan-Meier method.>>39<<" . . _:b16832039 "27 Such long lasting effects were also observed in lymphopenic cancer patients where T cell counts increased few weeks after the IL-7 cycle and remaind stable.6,>>24<<" . _:b497089008 . . _:b16832043 "As the study enrolled only previously untreated patients, lymphopenia or divpenia do not result from previous exposure to cytotoxic agents as described by others.30,>>31<<" . _:b497089005 . . . _:b497089043 . _:b16832036 "In contrast, accumulated evidences in clinical trials, indicate the potent lymphopoietic effect of rhIL-7 (CYT107, Cytheris), on both CD4+ and CD8+ T-cells subsets excluding Treg expressing low levels of IL-7R\u03B1 receptor.>>26<< Interestingly, in HAART resistant HIV individuals presenting with low CD4+ T cell counts (0,25 Giga/L), a short period of rhIL-7 treatment increased and maintained their CD4+ T cell pool above the > 0,5 Giga/L threshold for one year." . _:b497089036 . _:b16832027 . . _:b497088993 . _:b497088952 . _:b497089046 . _:b497089018 . _:b497088971 . _:b497089010 . _:b497089047 . _:b497089044 . _:b16832028 _:b16832029 . _:b16832028 _:b16832030 . _:b16832028 _:b16832031 . _:b497088953 . _:b16832030 . _:b497088998 . _:b16832026 _:b16832027 . _:b497088980 . _:b497088962 . _:b16832011 . . . . _:b16832022 _:b16832024 . _:b16832028 _:b16832048 . _:b16832022 _:b16832025 . _:b16832028 _:b16832049 . _:b16832028 _:b16832050 . _:b16832028 _:b16832051 . _:b16832027 . _:b497089029 . _:b497089035 . _:b16832022 _:b16832023 . . . _:b497089028 . . _:b16832028 _:b16832036 . _:b16832028 _:b16832037 . _:b497089031 . _:b16832028 _:b16832038 . _:b16832028 _:b16832039 . _:b497089023 . _:b16832028 _:b16832032 . _:b16832028 _:b16832033 . _:b497089030 . _:b16832028 _:b16832034 . _:b497089037 . _:b16832028 _:b16832035 . _:b16832013 "However, tumors develop escape mechanisms including production of immunosuppressive cytokines, alteration of dendritic cell subsets differentiation or function,8-10 and recruitment of immunosuppressive regulatory T-cells (Treg).>>11<<" . _:b16832028 _:b16832044 . _:b16832028 _:b16832045 . _:b497089025 . _:b16832028 _:b16832046 . _:b16832028 _:b16832047 . . _:b16832028 _:b16832040 . _:b16832028 _:b16832041 . _:b16832034 . _:b497089024 . _:b16832028 _:b16832042 . . _:b16832028 _:b16832043 . _:b497089027 . . _:b497089026 . . _:b16832045 . _:b497089037 . _:b497088956 . _:b497089036 . _:b497089039 . _:b16832005 "outcomes. In a series of studies gathering more than 3,000 patients, our group demonstrated that lymphopenia is observed in 20\u201325% of patients with advanced cancers, including 20% of untreated metastatic breast cancer (MBC) patients.>>1<<-4 All lymphocyte compartments are affected including CD4+ and CD8+ T lymphocytes, NK cells, and B lymphocytes." . _:b16832016 . _:b497089038 . _:b497089033 . _:b497089032 . _:b16832020 . . _:b16832004 _:b16832020 . _:b16832043 . _:b497088958 . _:b16832040 "27 Such long lasting effects were also observed in lymphopenic cancer patients where T cell counts increased few weeks after the IL-7 cycle and remaind stable.6,24,>>28<<" . _:b16832004 _:b16832021 . _:b497089035 . _:b497089034 . _:b16832004 _:b16832016 . _:b497088986 . _:b16832004 _:b16832017 . _:b497089034 . _:b16832004 _:b16832018 . _:b16832004 _:b16832019 . _:b497089045 . _:b497089006 . _:b497089044 . _:b497088941 . _:b16832004 _:b16832005 . _:b497089047 . _:b16832013 . _:b16832004 _:b16832006 . _:b497088987 . _:b16832004 _:b16832007 . . _:b497089031 . _:b497089046 . . _:b16832004 _:b16832012 . _:b16832004 _:b16832013 . _:b497089041 . _:b16832004 _:b16832014 . _:b16832004 _:b16832015 . _:b16832004 _:b16832008 . _:b16832004 _:b16832009 . . _:b497089040 . _:b16832004 _:b16832010 . _:b16832004 _:b16832011 . . _:b497089043 . . _:b497089042 . _:b497089053 . _:b497089052 . . _:b497088973 . . _:b497089054 . . . _:b497089049 . _:b497089048 . _:b497089051 . _:b16832035 . _:b497089050 . _:b497089029 "2"^^ . _:b497088946 . . . _:b497088954 . . _:b497089028 "2"^^ . . _:b497089031 "2"^^ . _:b16832018 . _:b497089030 "2"^^ . _:b16832025 . _:b497089025 "2"^^ . _:b16832004 . . _:b16832005 . _:b497089024 "2"^^ . _:b497088944 . _:b16832006 . _:b497089027 "2"^^ . _:b16832007 . _:b497089026 "2"^^ . _:b497088961 . _:b497089037 "2"^^ . _:b497088970 . . _:b497089036 "2"^^ . . _:b497089039 "2"^^ . _:b497088976 . _:b497089038 "2"^^ . . _:b497088974 . _:b16832012 . . _:b497089033 "2"^^ . _:b497088948 . . _:b16832013 . _:b16832017 "The T-cell receptor (TCR) combinatorial diversity results from mechanisms by which exons encoding TCR variable regions are assembled in developing T lymphocytes from germline variable (V), diversity (D), and joining (J) gene segments.>>15<<,16 Genomic V(D)J rearrangements leading to combinatorial diversity is of fundamental importance for the generation of diverse antigen receptor repertoires." . _:b497089032 "2"^^ . _:b497089053 . _:b497088979 . . _:b16832014 . _:b497089035 "2"^^ . . _:b16832015 . _:b497089034 "2"^^ . _:b497089015 . _:b497088942 . _:b16832036 . _:b16832008 . _:b497089045 "2"^^ . _:b497089003 . . _:b16832009 . _:b497089044 "2"^^ . . . _:b16832010 . _:b497089047 "2"^^ . . _:b16832040 . _:b16832012 . _:b16832011 . _:b497089046 "2"^^ . . _:b16832020 . _:b497089041 "2"^^ . _:b16832021 . _:b497089040 "2"^^ . _:b16832017 . . _:b497089049 . _:b497089043 "2"^^ . _:b16832022 . _:b497089038 . _:b497088981 . _:b16832012 . _:b16832023 . _:b497089042 "2"^^ . _:b497088966 . _:b497089001 . . . _:b16832016 . . _:b497089053 "2"^^ . _:b16832017 . _:b497089052 "2"^^ . _:b16832018 . _:b16832005 . _:b16832019 . _:b497089054 "2"^^ . _:b497089049 "2"^^ . _:b16832028 . . . _:b16832029 . _:b497089048 "2"^^ . _:b16832015 "The recent success of immunotherapy based on anti CTLA-4 antibodies inducing increased overall survival (OS)>>13<< in advanced melanoma confirms the relevance of T cell based anti tumor immunity (for review, see ref." . _:b497089011 . _:b16832030 . _:b497089051 "2"^^ . _:b16832031 . _:b497089050 "2"^^ . _:b16832024 . _:b497088943 . _:b16832025 . _:b16832026 . . _:b16832027 . _:b497088972 . . _:b16832036 . _:b16832031 . _:b16832037 . _:b16832038 . _:b16832029 . _:b16832039 . _:b497089017 . "PMC0" . _:b16832032 . _:b16832025 "of NDL in the models was evaluated using a likelihood ratio test (LRT); likelihood scores of the model evaluated with and without the biomarker were compared, considering that lower likelihood scores will indicate better fitting models.>>41<<" . _:b16832020 "receptor repertoires.17-19 Several studies demonstrate the importance of this diversity in infectious diseases and in anti-tumor responses. Indeed, constriction of the immune TCR repertoire has been associated with progression in AIDS.>>20<< In melanoma, a progressive widening of the repertoire diversity under chemo-immunotherapy treatment was accompanied by high avidity and tumor reactivity of Melan-A-specific T-cell clones." . _:b16832033 . . _:b16832034 . _:b497089044 . _:b497089045 . _:b497089046 . _:b16832035 . _:b497089047 . _:b497089040 . . _:b497089041 . _:b497089042 . _:b16832044 . _:b497089043 . _:b497089052 . _:b497089048 . _:b497089053 . _:b497089054 . _:b16832045 . _:b497088959 . _:b497089039 . _:b497089048 . _:b16832033 "enrolled in a prospective clinical trial (LYMPHOS1: NCT01306188) to confirm the prognostic value of lympho-divpenia in diverse clinical situations since we demonstrated that lymphopenia has a negative impact in different solid tumors.>>6<<" . _:b497089028 . _:b497089049 . _:b497089050 . _:b16832046 . _:b497089051 . _:b497089028 . _:b497089029 . _:b497089030 . _:b16832047 . _:b16832024 "Independent prognostic variables of OS were identified by a Cox regression analysis using a backward selection procedure.>>40<< The added value of NDL in the models was evaluated using a likelihood ratio test (LRT); likelihood scores of the model evaluated with and without the biomarker were compared, considering that lower likelihood scores will indicate better" . _:b497089031 . _:b497089024 . _:b497089025 . _:b497089026 . _:b16832040 . _:b497089027 . _:b497089036 . _:b497089037 . _:b16832044 "Thus reduced thymic function in elderly>>32<< may contribute to the reduced number and TCR diversity of circulating lymphocytes in tumor bearing patients." . _:b497089038 . _:b16832041 . _:b497089039 . _:b497089032 . _:b497088940 . _:b497089033 . _:b497089034 . _:b16832042 . _:b497089035 . . _:b16832037 "Interestingly, in HAART resistant HIV individuals presenting with low CD4+ T cell counts (0,25 Giga/L), a short period of rhIL-7 treatment increased and maintained their CD4+ T cell pool above the > 0,5 Giga/L threshold for one year.>>27<< Such long lasting effects were also observed in lymphopenic cancer patients where T cell counts increased few weeks after the IL-7 cycle and remaind stable." . _:b16832043 . _:b497088941 "5"^^ . _:b497088983 . _:b16832027 . _:b497089022 . _:b497088940 "6"^^ . _:b497088960 . _:b497088943 "5"^^ . _:b16832047 . . _:b497088942 "5"^^ . . . _:b497089013 . _:b16832048 . . _:b16832049 . _:b16832010 . _:b16832050 . . _:b497088949 "4"^^ . _:b16832051 . _:b16832009 . _:b497088948 "4"^^ . _:b497088949 . _:b497088951 "3"^^ . _:b497088950 "4"^^ . . _:b497088945 "4"^^ . _:b497088992 . . . _:b497088944 "5"^^ . _:b16832024 . _:b497088947 "4"^^ . _:b497088965 . . _:b497088946 "4"^^ . _:b16832044 . . . _:b497088957 "3"^^ . _:b16832051 . . _:b497088956 "3"^^ . . _:b497089000 . _:b497088959 "3"^^ . _:b497088958 "3"^^ . . _:b497088953 "3"^^ . _:b497088952 "3"^^ . _:b497088955 "3"^^ . . _:b16832004 . . _:b497088954 "3"^^ . _:b497088965 "3"^^ . _:b497088964 "3"^^ . . _:b497088967 "3"^^ . _:b16832022 . _:b497088966 "3"^^ . _:b497088961 "3"^^ . _:b16832028 . _:b497088960 "3"^^ . _:b497089025 . _:b16832026 . _:b497088963 "3"^^ . _:b497088962 "3"^^ . _:b497088973 "3"^^ . _:b16832010 "is also associated with an increased risk of disease progression and worse long-term survival in three prospectively collected series of patients with MBC at first line, along with non-Hodgkin lymphoma, and soft tissue sarcomas.>>6<<" . _:b497089024 . _:b497088972 "3"^^ . _:b497088975 "2"^^ . _:b497088974 "3"^^ . _:b497088969 "3"^^ . _:b497088968 "3"^^ . _:b497088971 "3"^^ . . _:b16832030 "On top of the well-documented negative impact of lymphopenia on OS for MBC patients and other advanced solid tumors,6,22,>>23<< these results further demonstrate that TCR diversity is frequently reduced in a subset of MBC patients and that divpenia may be assessed in clinic to better define the treatment strategy." . _:b16832045 "In this context, Mackall and colleagues>>31<< demonstrated the rapid CD4+ T cell pool reconstitution in young cancer patients treated with intensive chemotherapy." . _:b497088970 "3"^^ . _:b497088981 "2"^^ . _:b497088980 "2"^^ . _:b497088983 "2"^^ . _:b497088982 "2"^^ . _:b16832038 . _:b497088977 "2"^^ . _:b497088941 . . . . _:b497088976 "2"^^ . _:b497088940 . . _:b497088979 "2"^^ . . _:b497088943 . _:b497088978 "2"^^ . _:b16832042 . _:b497088942 . _:b16832004 "introduction" . _:b497088989 "2"^^ . _:b497088999 . _:b16832033 . _:b497088988 "2"^^ . _:b16832029 "On top of the well-documented negative impact of lymphopenia on OS for MBC patients and other advanced solid tumors,>>6<<,22,23 these results further demonstrate that TCR diversity is frequently reduced in a subset of MBC patients and that divpenia may be assessed in clinic to better define the treatment strategy." . _:b497088991 "2"^^ . _:b497088990 "2"^^ . _:b16832050 "Moreover, this lymphopenia could also result from a chronic stimulation of peripheral T cells favored by tumor cells leading to their depletion by activation induced cell death (AICD).>>37<< In this context, in HIV infection, CD4+ lymphopenia resulted from AICD due to chronic activation of the immune system by HIV infection, endotoxinemia or other cues rather than a direct destruction of infected CD4+ T cells (for review see" . . _:b497088985 "2"^^ . _:b497088949 . . _:b497088984 "2"^^ . _:b497088948 . _:b497088987 "2"^^ . _:b16832023 . _:b497088951 . . _:b497088986 "2"^^ . _:b497088950 . . _:b497088997 "2"^^ . _:b497088945 . _:b16832019 . . . _:b497088996 "2"^^ . _:b497088988 . _:b497088944 . _:b497088999 "2"^^ . _:b497088947 . . _:b497088998 "2"^^ . _:b497088946 . _:b16832019 . . _:b497089030 . _:b497088993 "2"^^ . _:b497088957 . _:b497089040 . _:b497088992 "2"^^ . _:b497088956 . _:b497088989 . _:b16832011 "of immune cells in solid tumors that may promote both humoral and cellular antitumor immune responses, contributing to tumor control. Indeed, high numbers of CD8+ T cells infiltrating breast tumor predict favorable clinical outcome.>>7<< However, tumors develop escape mechanisms including production of immunosuppressive cytokines, alteration of dendritic cell subsets differentiation or function,8-10 and recruitment of immunosuppressive regulatory T-cells (Treg)." . _:b497088995 "2"^^ . _:b497088959 . _:b16832034 "enrolled in a prospective clinical trial (LYMPHOS1: NCT01306188) to confirm the prognostic value of lympho-divpenia in diverse clinical situations since we demonstrated that lymphopenia has a negative impact in different solid tumors.6,>>23<<" . _:b497088994 "2"^^ . _:b497088958 . _:b497088977 . _:b497089005 "2"^^ . _:b497088953 . _:b16832026 "results" . _:b497089004 "2"^^ . _:b497088952 . _:b497088957 . _:b497089007 "2"^^ . _:b497088955 . _:b16832006 "is observed in 20\u201325% of patients with advanced cancers, including 20% of untreated metastatic breast cancer (MBC) patients.1-4 All lymphocyte compartments are affected including CD4+ and CD8+ T lymphocytes, NK cells, and B lymphocytes.>>3<< Importantly, in MBC patients lymphopenia in combination with PS > 1, is associated with a 20% risk of early death at 1\u00A0mo and 50% risk at 3\u00A0mo." . _:b497089006 "2"^^ . _:b497088954 . _:b497089001 "2"^^ . _:b497088965 . . . _:b497089000 "2"^^ . _:b497088964 . _:b497089003 "2"^^ . _:b497088967 . _:b497089002 "2"^^ . _:b497088966 . _:b497088947 . _:b497089013 "2"^^ . _:b497088961 . . _:b497089012 "2"^^ . _:b497088960 . _:b497089015 "2"^^ . _:b497088963 . _:b497089014 "2"^^ . _:b497088962 . . _:b497089009 "2"^^ . _:b497088973 . _:b497089008 "2"^^ . _:b497088972 . _:b16832027 "The incidence of lymphopenia (< 1 Giga/L) was 39% and 45% respectively for cohorts A and B higher than in previous series.>>1<<-4 In both cohorts, lymphopenia was associated with OS, with a median OS of 11.2 and 10.4 mo, vs." . _:b497089011 "2"^^ . _:b497088975 . _:b497088967 . _:b497089010 "2"^^ . _:b497088974 . . _:b497089012 . _:b497089021 "2"^^ . _:b497088948 . . _:b497088949 . _:b497088969 . _:b497088950 . . . _:b497088951 . _:b497089020 "2"^^ . _:b497089014 . _:b497088944 . _:b497088968 . _:b497088945 . _:b497088946 . _:b497089026 . _:b16832051 "context, in HIV infection, CD4+ lymphopenia resulted from AICD due to chronic activation of the immune system by HIV infection, endotoxinemia or other cues rather than a direct destruction of infected CD4+ T cells (for review see ref. >>38<<)." . . _:b497088947 . _:b497089023 "2"^^ . _:b497088956 . _:b497088971 . _:b497088957 . _:b497088958 . _:b497088959 . _:b497089022 "2"^^ . _:b497088952 . . _:b497088970 . _:b497088953 . _:b497088954 . _:b497088955 . _:b497089017 "2"^^ . . _:b497088950 . _:b497088981 . _:b497089032 . _:b497089016 "2"^^ . _:b497088980 . _:b16832037 . _:b497089019 "2"^^ . _:b16832014 . _:b497088940 . _:b497088983 . . _:b497088941 . _:b497088942 . _:b16832009 "3 Importantly, in MBC patients lymphopenia in combination with PS > 1, is associated with a 20% risk of early death at 1\u00A0mo and 50% risk at 3\u00A0mo.3,5,>>6<< In addition, lymphopenia is also associated with an increased risk of disease progression and worse long-term survival in three prospectively collected series of patients with MBC at first line, along with non-Hodgkin lymphoma, and soft" . _:b497088943 . _:b497089018 "2"^^ . _:b497088982 . _:b497088977 . _:b497088976 . . _:b497088979 . . _:b497088978 . _:b16832008 . _:b497089002 . . _:b497088989 . . . _:b497088968 . _:b497088988 . _:b16832014 "However, tumors develop escape mechanisms including production of immunosuppressive cytokines, alteration of dendritic cell subsets differentiation or function,8-10 and recruitment of immunosuppressive regulatory T-cells (Treg).11,>>12<<" . . _:b497088991 . . _:b497088975 . _:b497088990 . _:b497089012 . _:b497088985 . _:b16832049 . _:b16832049 "pro-apoptotic ligands,34 a blockade of lymphocyte proliferation via inhibitory molecules (PD-L1) expressed by tumor cells,35 or a reduced capacity of lymphocytes to respond to TCR stimulation due to an alteration of \u03B6 chain expression.>>36<< Soluble factors secreted or induced by tumor cells may also impact systemic lymphopoiesis." . _:b497089013 . _:b497089014 . _:b497089015 . _:b497089008 . _:b497088963 . _:b497089009 . _:b497088984 . _:b497089010 . _:b497089011 . _:b497089020 . . _:b497089029 . _:b497089021 . _:b497088987 . _:b497089022 . _:b497089023 . _:b497089016 . _:b497088986 . _:b497089017 . _:b497089018 . _:b497089019 . _:b497088996 . _:b497088997 . _:b497088997 . _:b497088998 . _:b497088999 . . _:b497088992 . _:b497088996 . _:b497088993 . _:b16832028 "discussion" . _:b497088951 . _:b497088994 . _:b497088995 . _:b497089004 . _:b497088999 . . _:b497089005 . _:b497089006 . _:b497089007 . _:b497089000 . _:b497088998 . _:b497089001 . . _:b497089002 . _:b497089003 . _:b497088980 . . _:b497088993 . _:b497088981 . _:b497088982 . . _:b497088983 . . _:b497088976 . _:b497088992 . _:b497088977 . _:b497088978 . _:b497088979 . _:b497088988 . _:b16832046 "regulating the peripheral T-cell pool size during anti-retroviral therapy. Indeed, number of polymorphisms in these genes, alone or in combination, and several haplotypes were found associated with the magnitude of CD4+ T-cell recovery.>>33<< Analyses of polymorphisms may help to elucidate mechanisms underlying lymphopenia in our study." . . _:b497088995 . _:b16832015 . _:b497088989 . _:b497088990 . _:b497088991 . _:b497089054 . _:b497088984 . _:b497088994 . _:b497088985 . . _:b497088986 . _:b16832050 . _:b497089020 . _:b497088987 . _:b497088964 . _:b497089005 . _:b497088965 . . _:b497088966 . _:b497088967 . _:b16832022 "materials and methods" . _:b497088960 . _:b497089004 . _:b497088961 . _:b497088985 . _:b497088962 . _:b497088963 . _:b497088972 . _:b497089007 . _:b497088973 . _:b497088974 . . _:b497088975 . _:b497088968 . _:b497089006 . _:b497088969 . _:b497089042 . _:b16832035 "favor CD4+ T-cell expansion, two clinical trials (SILCAAT and ESPRIT) performed in HIV individuals failed to demonstrate any clinical benefit, perhaps because of a concomitant expansion of Treg endowed with immunosuppressive functions.>>25<<" . _:b497088970 . _:b497088971 . _:b497089001 . _:b497089000 . _:b497089003 . _:b497088964 . _:b497089002 . . _:b497088969 . _:b497089013 . . _:b497089012 . _:b497089045 . . _:b497088997 . _:b16832041 "IL-7 therapy could also favor TCR diversity as recently demonstrated in HIV patients.>>29<< The impact of CYT-107 in the restoring lymphocyte counts and TCR repertoire diversity patients is currently under investigation in MBC in our institution in a randomized Phase II trial (ELYPSE 7 clinical trial, NCT01368107)." . _:b497089041 . _:b497089015 . _:b497089014 . . . _:b497089009 . . _:b497089008 . _:b497089011 . _:b497089010 . _:b497089021 . . _:b497089020 . . _:b497089027 . _:b497089023 . . . . _:b497089022 . _:b16832019 "from germline variable (V), diversity (D), and joining (J) gene segments.15,16 Genomic V(D)J rearrangements leading to combinatorial diversity is of fundamental importance for the generation of diverse antigen receptor repertoires.>>17<<-19 Several studies demonstrate the importance of this diversity in infectious diseases and in anti-tumor responses." . . _:b497089017 . _:b16832048 "reduced thymic function but also from the destruction of lymphocytes elicited by breast tumor cells expressing pro-apoptotic ligands,34 a blockade of lymphocyte proliferation via inhibitory molecules (PD-L1) expressed by tumor cells,>>35<< or a reduced capacity of lymphocytes to respond to TCR stimulation due to an alteration of \u03B6 chain expression." . . . _:b497089016 . . _:b497089019 . _:b497089018 .