In human breast carcinomas, overexpression of the macrophage colony–stimulating factor (CSF-1) and its receptor (CSF-1R) correlates with poor prognosis. To establish if there is a causal relationship between CSF-1 and breast cancer progression, we crossed a transgenic mouse susceptible to mammary cancer with mice containing a recessive null mutation in the CSF-1 gene (Csf1op) and followed tumor progression in wild-type and null mutant mice. The absence of CSF-1 affects neither the incidence nor the growth of the primary tumors but delayed their development to invasive, metastatic carcinomas. Transgenic expression of CSF-1 in the mammary epithelium of both Csf1op/Csf1op and wild-type tumor-prone mice led to an acceleration to the late stages of carcinoma and to a significant increase in pulmonary metastasis. This was associated with an enhanced infiltration of macrophages into the primary tumor. These studies demonstrate that the growth of mammary tumors and the development to malignancy are separate processes and that CSF-1 selectively promotes the latter process. CSF-1 may promote metastatic potential by regulating the infiltration and function of tumor-associated macrophages as, at the tumor site, CSF-1R expression was restricted to macrophages. Our data suggest that agents directed at CSF-1/CSF-1R activity could have important therapeutic effects.

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Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy.

Publisher Summary Autoantibodies to nuclear antigens (ANAs) have assumed an important place in the diagnostic armamentarium of the clinician because of distinct profiles of ANAs in different diseases. Profiles of ANAs have, therefore, been extremely useful in differential diagnosis, where the disease does not have classical or full-blown manifestations.. Immune complexes formed in the circulation or in situ mediate tissue injury by the activation of complement and other inflammatory mediators. Not only do these antibodies precipitate their respective antigens but also other proteins or nuclear RNAs that might be associated with them in special ways. The reasons for these special associations of protein antigens with specific sets of nuclear RNAs is unknown, but the possibility that there might be functional relationships in these complexed particles is not unreasonable. The key question that pervades the minds of many investigators in this field is the reason for the appearance of ANAs in certain individuals. It is highly improbable that the phenomenon is a random immune response to nuclear breakdown products, because the types of ANAs in different diseases are strikingly different. Some known environmental agents are drugs, such as hydralazine and procainamide, that together with lower levels of hepatic acetyltransferase enzyme predispose the host to the development of ANAs. Another agent may be the Epstein–Barr virus that is a ubiquitous environmental agent.

Autoantibodies to nuclear antigens (ANA): their immunobiology and medicine.

Purpose
Tumor associated macrophages (TAMs) are considered with the capacity to have both negative and positive effects on tumor growth. The prognostic value of TAM for survival in patients with solid tumor remains controversial.

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Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature.

Aluminum compounds as vaccine adjuvants

The peptide binding specificities of HLA-DRB1*0401, DRB1*0101, and DRB1*0701 have been analyzed by the use of large collections of synthetic peptides corresponding to naturally occurring sequences. The results demonstrated that nearly all peptides binding to these DR molecules bear a motif characterized by a large aromatic or hydrophobic residue in position 1 (Y, F, W, L, I, V, M) and a small, noncharged residue in position 6 (S, T, C, A, P, V, I, L, M). In addition, allele-specific secondary effects and secondary anchors were defined, and these parameters were utilized to derive allele-specific motifs and algorithms. By the combined use of such algorithms, peptides capable of degenerate DRB1*0101, DRB1*0401, and DRB1*0701 binding were identified. Additional experiments utilizing a panel of quantitative assays specific for nine additional common DR molecules identified a large set of DR molecules, which includes at least the DRB1*0101, DRB1*0401, DRB1*0701, DRB5*0101, DRB1*1501, DRB1*0901, and DRB1*1302 allelic products, characterized by overlapping peptide-binding repertoires. These results have implications for understanding the molecular interactions involved in peptide-DR binding, as well as the genetic and structural basis of MHC polymorphism. These results also have potential practical implications for the development of epitope-based prophylactic and therapeutic vaccines.

Several Common HLA-DR Types Share Largely Overlapping Peptide Binding Repertoires

Adjuvants--a balance between toxicity and adjuvanticity.

This review describes the potential role of macrophages in defense against cancer cells and the regulatory involvement of inflammatory mediators in this role. Interactions between macrophage-derived cytokines (tumor necrosis factor alpha, interleukin-1, IL-6) and their interrelationships with eicosanoids (mainly the cyclooxygenase product prostaglandin E2 and some lipoxygenase metabolites) represent a network that controls the expression of antitumor activity of macrophages either in a cell-to-cell contact system between the effector and the target tumor cell or as cell-free soluble products. Attention is given to the influence of tumor burden on production of cytokines and eicosanoids by macrophages and to the production of these mediators by tumor cells. Emphasis is placed on the roles of TNF-alpha and PGE2 in links between inflammatory and antitumor functions of macrophages. Finally, the perspectives and still existing problems in clinical implications of macrophage-derived cytokines are discussed in terms of a conceivable macrophage-directed immunotherapy of cancer.

Involvement of inflammatory mediators in macrophage antitumor activity.

The prognostic significance of immunocompetence determined at diagnosis was analyzed in 158 operable breast cancer patients followed for 3--6 years, in terms of disease recurrence and of length of disease-free period (DFP) and in 52 patients with metastatic disease in terms of length of survival. In vitro lymphocyte stimulation by PPD and PHA were of higher predictive value with respect to probability of disease recurrence than in vivo cutaneous reactivity to PPD and DNCB. Conversely, length of DFP and of survival were found to correlate better with in vivo than within vitro parameters. Absolute number of peripheral blood lymphocytes (PBL) and percent of E-rosette-forming cells (E-RFC) proved devoid of prognostic value. Prognostic separation was best brought out upon analysis by integrated score of immunocompetence, comprising the four functional parameters. Probability of disease recurrence was 0.43 for all operable patients, as calculated by actuarial method 48 months postoperatively; it was 0.26 for optimal and 0.61 for suboptimal responders (P less than 0.0001). Separate analysis of Stage 1 (N0) and Stage II (N+) patients revealed prognostic segregation within each stage: probability of recurrence in Stage I was 0.06 for optimal vs. 0.41 for suboptimal responders (P less than 0.001) and in Stage II it was 0.45 vs. 0.79, respectively (P less than 0.01). These findings may prove valuable for a more selective patient allocation for post-mastectomy adjuvant therapy. Length of DFP was found inversely proportional to initial immunocompetence, with a mean of 23.5 months for good responders and 12.8 months for poor responders (P less than 0.01). Length of survival of metastatic patients was found to correlate with initial (pretreatment) levels of immunocompetence, mean survival being 29.5 months for those with preserved immune function and 12.3 months for the immunosuppressed (P less than 0.001). It was concluded that initial immunocompetence, determined by parameters of cell-mediated immunity, shows strong prognostic association with the subsequently observed course of human breast cancer.

Immunocompetence, immunosuppression, and human breast cancer. III. Prognostic significance of initial level of immunocompetence in early and advanced disease

Experimental studies on the mechanism of induction of anti-nuclear antibodies by procainamide

Comprehensive immune function by integrated score was assessed in 158 operable, 55 inoperable, and 52 metastatic breast cancer patients relative to 107 healthy controls. The score was derived from in vivo response to PPD and DNCB and in vitro lymphocyte stimulation by PPD and PHA. Proportion of E-RFC was significantly lower in patients than in controls but was not found to correlate directly with the above functional criteria. Fifty-one percent of the patients with early, operable tumors were shown to be at least partially immunosuppressed by integrated score achievement vs. 11% of controls. This proportion rises to 68% of inoperable and 89% of metastatic patients. Quantitative analysis by graded response revealed an additional, significant degree of immune impairment in the respective patient groups by all testing parameters. Depression of immune function in operable patients was not related to age nor influenced by surgery. Immunocompetence of patients with mammary dysplasia did not differ from controls. Increasing size of primary tumor (T) was not found to be matched by progressive degree of immunosuppression, excepting that associated with large T4 tumors. Patients with lymph node involvement (N+) were not significantly immunologically inferior to those without (N0) where the larger operable T2-3) tumors are concerned. In the smallest, T1 tumors, nodal involvement (N+) is accompanied by remarkable immunosuppression relative to T1N0 cases. This finding suggests a pre-existing immune defect inherent in T1N+ patients. It supports the hypothesis that the immunosuppression associated with early breast cancer is primary, patient related. Secondary tumor-induced depression of immune response characterizes advanced and metastatic human breast cancer.

Immunocompetence, immunosuppression, and human breast cancer. II. Further evidence of initial immune impairment by integrated assessment effect of nodal involvement (N) and of primary tumor size (T)

Shlomo Ben-Efraim

Papers

Adjuvants--a balance between toxicity and adjuvanticity.

Involvement of inflammatory mediators in macrophage antitumor activity.

Immunocompetence, immunosuppression, and human breast cancer. III. Prognostic significance of initial level of immunocompetence in early and advanced disease

Experimental studies on the mechanism of induction of anti-nuclear antibodies by procainamide

Immunocompetence, immunosuppression, and human breast cancer. II. Further evidence of initial immune impairment by integrated assessment effect of nodal involvement (N) and of primary tumor size (T)