Breast cancer remains a leading cause of cancer-related death within the female population. Immunotherapy is expected to provide additional therapeutic benefits but has met so far limited success. This may be due in part to the poor understanding of immune responses to breast cancer. Although CD4 1 and CD8 1 T lymphocytes infiltrate these tumors, the phenotype and functions of these cells remain ill defined. This study was designed to investigate further about these questions, taking advantage of multiparameter flow cytometry on lymphocytes derived from peripheral blood, solid tumors, metastatic lymph nodes and pleural effusions samples of patients with breast cancer. Results showed that, in addition to conventional CD4 1 and CD8 1 ab T cells, individual tumors and most pleural effusions contained significant fractions of unconventional double positive (DP) CD4 1 CD8 1 ab T cells. These DP T cells displayed the phenotype and cytotoxic potential of effector/memory activated CD8 1 T cells but differed essentially from these cells by a high production of IL-5 and IL-13. The increased frequency of DP T cells in advanced breast cancer and their high lytic potential and original cytokine profile suggest that this T-cell subset may play a specific role in the regulation of immune responses to human breast cancer. ' 2009 UICC

High level of T-cell infiltration in colorectal carcinomas (CRCs) is a good prognostic indicator, but the tumor reactivity of this infiltrate (tumor infiltrating lymphocytes [TIL]) is poorly documented. This study examined the presence, phenotype and functional features of tumor-reactive lymphocytes in human CRC. Freshly dissociated TIL and T cell lines were isolated from CRC samples and from some paired normal colonic mucosa. Four tumor cell lines were obtained. Autologous tumor reactivity of CRC TIL and tumor-reactive cell features were analyzed. We demonstrate the presence among CRC TIL of variable fractions (up to 18%) of double positive CD4 1 CD8ab 1 (DP) ab T cells. Interestingly, a high proportion (16-20%) of this TIL subset displayed tumor reactivity, whilst this was the case for no or few single positive TIL. Low levels of DP TIL were found in most CRC samples and in normal colonic mucosa, but these cells were higher in metastatic CRC. Furthermore, we showed that DP TIL were polyclonal, restricted by HLA class-I, proliferated poorly and secreted higher amounts of IL-4 and IL-13 than single positive T cells, on cognate or CD3 stimulation. DP CRC TIL also expressed CD103, confirming their mucosal origin. Increased frequencies of tumor-reactive DP TIL in metastatic CRC suggest that these cells play a role in the metastatic process of this cancer. Based on their high secretion of IL-4 and IL-13 and on previously described roles of these cytokines in cancers, we postulate that DP TIL could favor CRC growth or metastasis and/or downmodulate immune responses to these tumors.Recent studies have highlighted the high prognostic value of the density of T cells infiltrating colorectal carcinomas (CRC), implying an important contribution of T-cell responses to the control of this cancer. 1 Nonetheless, contrary to other cancers such as melanomas, 2 evidence that CRC may induce tumor-specific T-cell responses in an autologous setting is still scarce. 3 This may be due to the difficulty in obtaining stable CRC cell lines required for the detection of T cells specific to individual tumor antigens such as frameshift mutations. 4 Alternatively, it might result from the presence of qualitatively unique T-cell responses in this cancer, which has not yet been appropriately addressed.We previously reported that CRC-reactive c9d2 T cells were present in several CRC ascites. 5 The aim of the present study was to analyze the presence of conventional and unconventional tumor-reactive ab T cells, such as CD4 þ CD8 þ double positive cells (DP), in a significant series of CRC.As reviewed by Parel et al., 6 DP T lymphocytes account for a small and heterogeneous subset of TCRab cells. At present, three subsets of these cells could be distinguished: (i) conventional CD8 þ T cells that on activation express low CD4 levels; (ii) conventional CD4 þ T cells that acquire longterm CD8aa expression in vivo, as a result of exposure to unknown factors associated with the intestinal environment, aging or HIV infection and (iii) T cells stably e...

SummaryThe influence of polymorphisms of the glutathione S-transferase gene GSTM1 in breast cancer susceptibility has been assessed in this study. Previous studies correlated the absence of the GSTM1 protein with an increased risk of developing some cancers, especially lung or bladder cancers, in heavy smokers. In this study, we determined GSTM1 polymorphisms in a population of 437 female controls from the west of France and 361 community breast cancer patients. Three distinct alleles of this gene exist: GSTM1* A, GSTM1*B and GSTM1*0 (deleted allele). Null subjects (GSTM1 null) are homozygous for this deletion. The comparative analysis of GSTM1 allelotypes in our two populations did not demonstrate a statistically significant difference in distribution (P = 0.22), although the null genotype was more frequent in cancer patients. However, breast cancer risk was increased in null subjects ≥ 50 years of age compared with non-null subjects [odds ratio = 1.99 (1.19-3.32), P = 0.009], but not in null subjects < 50 years of age compared with non-null subjects (P = 0.86). Our results suggest that the GSTM1 null genotype may play a role in post-menopausal breast cancer development. They also point to a putative protective role of the A allele in the older female control group, especially in hemizygous subjects [odds ratio = 0.42 (0.23-0.77), P = 0.03].

This set of mature controlled data confirms the added value of anthracycline-based combination adjuvant therapy for N+ breast cancer patients when compared with CMF, with both regimens given for 1 year.

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