The Autoimmune Response In Lung Cancer Is Similar To That In The Systemic Autoimmune Diseases

A parallel can be drawn between the systemic autoimmune diseases and cancer in relation to the antinuclear antibodies observed in both conditions. In both, cellular proteins become antigenic targets of a humoral response. By far the most common autoantibodies

Table 1. Predicting ability of antinuclear antibodies. (The ability of antinuclear antibodies to predict lung cancer cell type, diagnosis, or progression-free survival were analyzed by cross-validated CART)

Correctly predicted Sensitivity Specificity

Cell type:

hg90, sm70, hgl 10, lg 160, hg65, qg85, agl80, ng55, sg30 50 n/a n/a

Lung cancer diagnosis: nm60, ami 15, nm200, hm55, lgl60, ag75, smlOO, agl80, ng55, qml05, qg200, hgl80 73 55 92

Progression-free survival: agl50(<4 months), am45, lgl80, hg65, or am70 (4-9 months),

Iml60,ng30,qgl60, or sm220(>9 months) 52 n/a n/a

Antigen variables selected by cross-validated CART analyses are presented and labeled with the first letter designating the antigen set (h, s, q, a, 1, n, for HeLa, small cell carcinoma, squamous cell carcinoma, adenocarcinoma, large cell carcinoma and normal lung cell, respectively); the second letter (g or m) designates the recognizing isotype IgG or IgM, and the following number designates the antigen size in kDa.

found in the systemic autoimmune diseases are those directed against nuclear antigens [8, 23-26, 56]. Attempts to show nuclear reactivity in patients with cancer using characterized antigens known to be involved in the immune response in the systemic autoimmune diseases have been unrewarding [14, 57]. The failure of cancer sera to recognize those antigens may merely reflect the presence of different specificities related to the cancer itself.

A characteristic profile of autoantibodies is found in each of the systemic autoimmune diseases. These autoantibodies are helpful in establishing a correct diagnosis and prognosis and frequently facilitate the follow-up and treatment of these patients. The value of these antibodies in the diagnosis of the systemic autoimmune diseases is related to their immunologic specificity. Similarly, our data suggest that some of the antinuclear antibodies found in lung cancer sera may be relatively tumor specific and can be predictive of outcome [54]. Autoantibodies frequently precede the onset of a systemic autoimmune disease such as SLE by many years [56]. The report of Frenkel et al. [58] of high titer antinuclear antibodies years before the diagnosis of cancer and the frequent finding of high titer IgG antinuclear antibodies at the time of diagnosis in patients with neoplasia in our work, suggests that an established immune response to some nuclear antigens can be demonstrated in cancer sera before the tumor is clinically evident.

An important feature of autoantibodies in systemic autoimmune diseases is their occurrence as linked sets. Antibodies to native DNA are frequently asso ciated with antibodies to histones, antibodies to Sm are frequently associated with antibodies to nuclear RNP (Ul-RNP) and antibodies to La/SS-B are often associated with antibodies to Ro/SS-A [24-26]. Autoantibodies in the systemic autoimmune disease are directed at antigens that are complexed to each other. For example DNA and histones occur together as nucleosomes, Sm and U1RNP are found together as nuclear particles called small nuclear ribonucleo-proteins (smRNPs), and La/SS-B and Ro/SS-A are complexed as intracellular particles.

There are also indications for the development of linked antibody response in cancer. In melanoma, multiple components of the melanosome, a cellular organelle found in melanocytes, have been reported to be recognized by autoantibodies [59]. Also, we have recently identified autoantibodies to the 32- and 14-kDa subunits of replication protein A (RPA) in the sera of patients with lung, breast and prostate cancer [42], These subunits of RPA are known to be a part of a multicomponent enzyme complex [41, 6062] involved in the metabolism of DNA [60, 63-68], Thus, our data suggest that autoantibodies developing in cancer patients, similar to those of the systemic autoimmune diseases, may be recognized multiple epitopes of immunogenic subcellular particles. This possibility deserves further investigation.

The wide occurrence of autoantibodies found by our work in cancer patients is similar to that in systemic autoimmune diseases and one could entertain the working hypothesis of a common immunopatho-genesis. In this light cancer could be hypothesized to be a family of systemic autoimmune diseases in which alteration of cellular oncogenes and tumor suppressor genes have led to deregulation of cell growth. As is true of the systemic autoimmune diseases, this model would imply that autoantibodies may appear in these subjects long before the clinical symptoms of cancer develop and that some of them could be laboratory indicators of therapeutic success or failure. This hypothesis can be tested by developing specific ELISAs using recombinant proteins as substrate and showing the tumor specificity and predictive ability of these autoantibodies. Experiments monitoring the development of the immune response in a well defined animal model of cancer could be revealing. Whether the repertoire of autoantibodies produced would reflect the ontogeny of the disease is an open question.

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