Host immune potentiation of drug responses to a murine mammary adenocarcinoma. II. Effect of melphalan therapy on the host immune system

The role of chemotherapy in influencing tumorspecific immunity to a mouse mammary adenocarcinoma was investigated. By studying different stages of tumor growth we were able to identify several factors important to drug-induced tumor regression: (1) antibody response, (2) delayed hypersensitivity, (3) sensitivity of tumor cells to immune attack and (4) tumor burden. The presence of tumor-specific delayed hypersensitivity and circulating antibody as well as specifically armed monocytes in the tumor mass characterize the T1699 adenocarcinoma. Successful chemotherapy had previously been shown to depend on prior establishment of the above immune responses. Treatment with alkylating agents was marked in all animals by abrogation of a humoral response to the tumor when drug was given early (day 7), and was associated with poor chemotherapeutic results. Later treatment (day 10) was associated with depression of antibody titers only in the minority of animals not responding to drug and prolongation of the delayed hypersensitivity response in all treated animals. Tumors recurring following initial drug-induced regression were marked by lack of delayed hypersensitivity in the host, lack of drug response and suppression of humoral immunity following treatment. Successive passage of cells from these resistant tumors led to decreasing sensitivity to chemotherapy despite established immunity on the part of the host. The selection of tumor cells resistant to immune destruction rather than drug resistance per se appeared to play a role. Melphalan was thus able to affect both favorably and adversely the immune factors important to drug-induced regression. Renforcement, Par Les Reactions Immunitaires De L'Hǒte, De La ChimiotherApie D'Un Adenocarcinome Mammaire Murin. II. Effet Du Traitement Au Melphalan Sur Le Systeme Immunitaire De L'hǒte Nous avons cherche a determiner l'influence de la chimiotherapie sur l'immunite tumorispecifique contre un adenocarcinome mammaire de souris. En etudiant les differents stades de la croissance tumorale, nous avons pu identifier plusieurs facteurs importants pour la regression chimio-induite de la tumeur: 1) la reponse des anticorps, 2) l'hypersensibilite retardee, 3) la sensibilite des cellules tumorales a l'attaque immunitaire et 4) la surcharge en tissu tumoral. La presence d'une hypersensibilite retardee specifique de la tumeur et de l'anticorps circulant ainsi que les monocytes specifiquement armes qui se trouvent dans la masse tumorale sont caracteristiques de l'adenocarcinome T1699. On avait deja demontre que le succes de la chimiotherapie dependait du declenchement prealable des reponses immunitaires susmentionnees. Le traitement aux agents alcoylants a ete marque chez tous les animaux par la suppression d'une reponse humorale a la tumeur lorsque le produit a ete administre tǒt (au jour 7); les resultats chimiotherapeutiques etaient alors mediocres. Lorsque le traitement est plus tardif (au jour 10), on constate que les titres d'anticorps ne diminuent que chez les quelques animaux qui ne reagissent pas au produit et que la reaction d'hypersensibilite retardee se prolonge chez tous les animaux traites. Si les tumeurs reparaissent apres une regression initiale induite par le produit, on n'observe plus d'hypersensibilite retardee chez l'hǒte, ni de reaction au produit, et l'immunite humorale disparaǐt apres le traitement. Des passages successifs des cellules provenant de ces tumeurs resistantes entraǐnent une diminution de la sensibilite a la chimiotherapie malgre l'immunite etablie de l'hǒte. C'est la selection de cellules tumorales resistant a la destruction immunitaire plutǒt que l'insensibilite au produit en elle-měme qui semble jouer un rǒle. Le Melphalan a donc un effet a la fois favorable et defavorable sur les facteurs immunologiques qui interviennent dans la regression chimio-induite.