Adoptive immunotherapy with cyclophosphamide (Cy) increases the host resistance against tumor growth. The precise mechanism(s) by which this therapy enhances tumor suppression is unclear. Cy induces the development of early myeloid cells that may be strongly antiproliferative through NO production. These cells are similar to the natural suppressor cells found in normal bone marrow with a potential antitumor effect. Here we have addressed whether the development of NO-producing cells may be involved in this tumor resistance in Cy-treated mice. The results show a synergism between Cy treatment and tumor-specific lymphocytes transferred systemically (i.v.) or locally (Winn’s assay) that results in a strong tumor suppression. Inhibition of NO production by NG-monomethyl-l-arginine at the site of tumor inoculation results in a loss of the protection achieved by the combined therapy. Cy-treated mice develop splenic early myeloid (CD11b, Gr-1, CD31 (ER-MP12), ER-MP20, ER-MP54) cells producing large amounts of NO upon T cell-derived signals (IFN-γ plus CD40 ligation) able to inhibit tumor cell growth in vitro. Early myeloid cells (ER-MP54+) and cells expressing inducible NO synthase are increased at the site of tumor challenge in mice treated with the combined therapy, but not in those treated with Cy or immune cell transfer alone. Thus, Cy induces the expansion of early myeloid cells, inhibiting tumor cell growth by a mechanism involving NO. Both the recruitment and the activation of these myeloid cells at the site of tumor challenge appear to be dependent on the presence of tumor-specific lymphocytes.

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Favorable prognosis in completely resected NSCLC is determined by a B-cell-mediated immune response. It can be differently scored by a 50-gene expression profile or by CD20 immunostaining. That prognosis information not reflected by traditional classifications may become a new tool for determining individualized adjuvant therapies.

Purpose: A subset of colorectal cancers (CRC) arises in families that, despite fulfilling clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), do not show evidence of a mismatch repair (MMR) deficiency. The main objective of this study was to characterize these tumors at the molecular level. Experimental Design: After comprehensive germ line mutation scanning, microsatellite analysis, and MMR protein expressions, we selected a well-defined cohort of 57 colorectal tumors with no evidence of MMR defects. In this group of tumors, we analyzed KRAS, BRAF, and APC somatic mutations, as well as methylguanine methyltransferase (MGMT) and h-catenin expression.We correlated these alterations with clinicopathologic data and explored the relationship between KRAS G > A transitions and lack of MGMTexpression. Results:The mutation profile at the RAS/RAF/MAPK pathway mimics sporadic microsatellitestable CRCs. We found an average age of diagnosis 10 years older in KRAS-mutated patients (P = 0.001). In addition, we show that KRAS G > A transitions are actively selected by tumors, regardless of MGMT status. Similarities with HNPCC high^microsatellite instability tumors are observed when APC data are analyzed. The APC mutation rate was low and small insertions/ deletions accounted for 70% of the alterations. In addition, we found a low frequency of h-catenin nuclear staining. Finally, we did not find evidence of tumors arising in individuals from the same family sharing molecular features. Conclusions: We show evidence that CRC tumors arising in HNPCC families without MMR alterations have distinctive molecular features. Overall, our work shows that systematic analysis of somatic alterations in a well-defined subset of CRCs is a good approach to provide new insights into the mechanisms of colorectal carcinogenesis.Approximately 5% of all colorectal cancers (CRC) are diagnosed in the context of known Mendelian syndromes, principally, hereditary nonpolyposis colon cancer (HNPCC) and familial adenomatous polyposis. When considering HNPCC as a syndrome linked to mismatch repair (MMR) gene mutations, the frequency range is from 0.3% to 3% of the total CRC burden (1). Tumors from patients with MMR mutations frequently show high -microsatellite instability (MSI-H; ref.2). The MSI-H phenotype is also found in 10% to 15% of sporadic CRCs, although these tumors differ from their hereditary counterparts at the molecular level (3, 4). For instance, the MMR deficiency seen in sporadic tumors is mainly due to hMLH1 promoter hypermethylation. Apart from MSI, less wellcharacterized genetic instability phenotypes may contribute to colorectal carcinogenesis. For example, epigenetic silencing of methylguanine methyltransferase (MGMT), leading to an excess of G > A transitions, is a common event (5).Early genetic events in colorectal carcinogenesis involve the deregulation of the WNT and RAS/RAF/MAPK pathways. The mutation profile of a particular tumor is related to the underlying phenotype instability. For example, in MSI...