From: bigoldberg@igc.apc.org (Billi Goldberg)
Newsgroups: sci.med.aids
Subject: Breast Cancer and the Immune System
Date: 20 Dec 92 21:16:51 GMT
Organization: unspecified
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6659


                  BREAST CANCER AND THE IMMUNE SYSTEM
                            Billi Goldberg

The "experts" have been working with all their abilities on the cure
for breast cancer. In 1960, 1 of 14 women in the US got breast cancer;
now the rate is 1 in 8. That is real progress. This wonderful increase
is only in the US. The question now becomes: Why? 

It is usually well-off women who can afford the "best" medical care
that get breast cancer. These "lucky" women have had such care
all of their life. Whenever they had problems with their health (major 
and minor), the doctors (I've been told) give them broad-spectrum 
antibiotics such as cefaclor (Ceclor) indiscriminately. These drugs are 
known immunosuppressants. Birth-control pills have been extremely 
popular during the last few decades and they are primarily progestin 
(progesterone) which is also immunosuppressive and especially affects 
the cell-mediated immune response. I understand that Jewish women have 
an especially high rate of breast cancer; they get the best "care" 
possible (I've been told). Older women past the menopause have a greater risk
of breast cancer. It is my understanding that such women have increased levels
of progestin and decrease levels of estrogen.
  
Abnormal or cancerous cell destruction depends on an effective cell-
mediated immune response to tumor antigens expressed on the Class I MHC 
of these cells. If you depress the CMI, you depress tumor surveillance.
Sounds just like AIDS. If you depress the CMI, the OI pathogens 
replicate uncontrollably. 

Is it possible that breast cancer is iatrogenic in origin?

Wouldn't it be interesting to get continuous T4 and T8 and NK counts in 
women with breast cancer and follow them as the cancer progresses?  
Especially interesting would be the T8 HLA-DR subset which is especially 
cytotoxic.

Rosenberg's research and trials at NCI utilized ex vivo expansion of 
lymphocytes (LAK, TIL) as a possible weapon against cancer. It has not 
been very successful but that could have been due to the ex vivo 
approach rather than immune modulation.
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Berger M; Irschick E; Fritsch E; Frommhold H; Schonitzer D; Wiegele J; 
Kemmler G; Huber C. Influence of local radiotherapy of breast cancer 
patients on the frequency of cytotoxic T lymphocyte precursor cells. 
Immunobiology, 1990 Feb, 180(2-3):261-71. 

Abstract: Alloantigen-specific cytotoxic T lymphocyte precursor (CTL-p) 
frequencies were analyzed in ten patients with histologically proven 
breast cancer receiving prophylactic RT. The frequency of CTL-p was 
assessed by limiting dilution (LD) analyses before, immediately after 
discontinuation of treatment and at various times following RT. The 
number of pbmnc, adherent cells and T cells was determined in parallel. 
Local RT led to a minor and transient reduction of CTL-p frequencies 
lasting approximately three months: on average a 25% decrease of CTL-p 
numbers was seen immediately after RT. Three months following treatment, 
a 20% reduction was still evident. Values subsequently returned to 
pretreatment levels. Moreover, these changes in the frequency of 
antigen-specific CTL were accompanied by a 25% to 39% decrease in the 
blood T cell counts lasting for more than 12 months. The reductions 
following local RT were less pronounced than those induced by 
immunosuppressive drugs in allograft recipients. 
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Hakim AA. Peripheral blood lymphocytes from patients with cancer lack 
interleukin-2 receptors. Cancer, 1988 Feb 15, 61(4):689-701. 

Abstract: When tumor cells develop in healthy adults, they activate the 
cellular immune system--natural killer (NK) cells, antigen-specific 
cytotoxic lymphocytes (CTL), and the synthesis of antigen specific 
cytotoxic antibodies. These are aimed at killing the intruding cells. 
However, in cancer patients the tumor continues to grow. As tumor cells 
proliferate, they were shown to release factors that mediate the 
inactivation of the host immune defense systems. The study documented in 
this article examined peripheral blood lymphocytes, mononuclear cells 
(MNC), NK cells, T-helper cells (THC). This study confirmed the 
interaction of the released inhibitor factors with these mononuclear 
cells. NULL cells from healthy adults responding to interleukin-2 (IL-2) 
and NILL cells from patients with metastatic breast carcinoma 
nonresponsive to IL-2 were also isolated by the standard antibodies-
pinning technique. The cells were obtained from age-matched subjects: 
ten healthy adults; ten patients each from Stage I, II, III, and IV 
metastatic breast carcinoma (BCa-I, BCa-II, BCa-III, and BCa-IV or 
MBCa); and ten patients with benign breast disease (BBD). The 
responsiveness of these THC, PBMNC, NK, NULL, and NILL cells in vitro to 
graded levels of phytohemagglutinin (PHA), Concanavalin A (Con A), and 
recombinant interleukin-2 (rIL-2) was examined. Responsiveness was 
monitored by 3H-thymidine (3H-TdR) uptake, production and release of 
IL-2, interleukin-2 receptor (IL-2R), and cytotoxic activities against 
K-562 cells and breast carcinoma short-term cell lines. A lack of 
functional IL-2R in peripheral blood lymphocytes from patients with 
metastatic breast carcinoma was confirmed by nonsignificant anti-Tac 
antibody binding. An elevation in the expression of cell surface antigen 
GP-120 has been observed to be associated with the activation in vitro 
of T-cells from healthy adults and from patients with benign breast 
disease, but not of T-cells from patients with breast carcinoma. 
Biochemical studies of the GP-120 using high performance liquid 
chromatography combined with nitrocellulose blotting confirmed that the 
glycoprotein was resistant to trypsin and chymotrypsin, but susceptible 
to pronase. It contained sialic acid and lactosaminoglycan as O-linked 
sugars. It could be labeled with pariodate/NaB(3H4) and is recognized by 
MAbT-305 monoclonal antibodies. It contained sialic acid linked (2---3) 
to galactose.(ABSTRACT TRUNCATED AT 400 WORDS) 
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Hakim AA. Peripheral blood lymphocytes from patients with cancer lack 
interleukin-2 (IL-2) receptor expression: isolation of mRNA encoding IL-
2R. Cancer Detection and Prevention, 1988, 12(1-6):59-71. 

Abstract: In healthy adults, tumor cells stimulate the cellular immune 
defense mechanisms: natural killer (NK), antigen-specific cytotoxic 
lymphocytes (CTL), and synthesis of antigen-specific cytotoxic 
antibodies, all aimed at the destruction of the intruding tumor cells. 
The experiments described in this study examined responsiveness of 
peripheral blood lymphocyte mononuclear (MNC) cells, natural killer (NK) 
cells, T-helper (THC) cells, and NILL (cells obtained from patients with 
advanced breast cancer) cells from 10 of each age-matched subjects from 
10 healthy adults and patients, 10 with benign breast diseases (BBD), 
and 10 from patients from each of the breast carcinoma pathological 
stage BCa PS I, BCa PS II, BCa PS III, and BCa PS IV. Cellular 
responsiveness to graded levels of phytohemagglutinin (PHA), 
concanavalin A (Con A), and recombinant interleukin-2(r IL-2) was 
monitored by 3H-thymidine (3H-TdRO) uptake, production, and release of 
interleukin-2 (IL-2) and interleukin-2 receptor (IL-2R) and cytotoxic 
activities against K-562 and breast carcinoma (BCa) short-term cell 
lines. Suppressed cellular responsiveness is caused by the lack of 
functional IL-2R in peripheral blood lymphocytes with metastatic breast 
carcinoma (MBCa). This is confirmed by suppression of the anti-Tac 
antibodies binding and lack of cellular mRNA encoding IL-2R. 
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Gereis M; Burford-Mason AP; Watkins SM. Suppression of in vitro 
peripheral blood lymphocyte mitogenesis by cytotoxic drugs commonly used 
in the treatment of breast cancer: a comparative study. Agents and 
Actions, 1987 Dec, 22(3-4):324-9. 

Abstract: Cultures of normal donor peripheral blood mononuclear cells 
were tested in vitro for suppression by chemotherapeutic agents or their 
metabolites. The drugs tested were those commonly used in the treatment 
of breast cancer, namely, 5-fluorouracil, doxorubicin, vincristine, 
methotrexate and cyclophosphamide (actually testing its active 
metabolite, 4-hydroxy-cyclophosphamide). The lymphocytes were stimulated 
by phytohaemagglutinin (PHA), and the inhibitory effect of the drugs on 
subsequent DNA synthesis was measured by tritiated thymidine uptake. 
Drug concentrations used were equivalent to expected in vivo plasma and 
body fluid levels following i.v. injection of a standard therapeutic 
dose. Results suggest that the drugs may be ranked for suppression of T-
cell function as follows: doxorubicin greater than vincristine = 
cyclophosphamide greater than 5-fluorouracil greater than methotrexate. 
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